5-alkynyl-pyrimidines

ABSTRACT

The present invention encompasses compounds of general formula (1) 
     
       
         
         
             
             
         
       
     
     wherein
 
R 1  to R 3  are defined as in claim  1 , which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and the use thereof for preparing a medicament having the above-mentioned properties.

The present invention relates to new 5-alkynyl-pyrimidines of generalformula (1)

wherein the groups R¹ to R³ have the meanings given in the claims andspecification, the isomers thereof, processes for preparing thesealkynyl-pyrimidines and their use as medicaments.

BACKGROUND TO THE INVENTION

A number of protein kinases have already proved to be suitable targetmolecules for therapeutic intervention in a variety of indications, e.g.cancer and inflammatory and autoimmune diseases. Since a high percentageof the genes involved in the development of cancer which have beenidentified thus far encode kinases, these enzymes are attractive targetmolecules for the therapy of cancer in particular.

The phosphoinositide 3-kinase (PI3K) pathway is activated in a broadspectrum of human cancers. This may occur either via mutation of PI3Kresulting in activation of the kinase, or indirectly via inactivation pfthe phosphotase and tensin homologue (PTEN) suppressor. In both cases,an activation of the signalling cascade is induced that promotestransformation of cells both in vitro and in vivo. Within the cascade,the Pi3K family of enzymes and the kinase mTOR play a pivotal role. ThePI3K family comprises 15 lipid kinases with distinct substratespecificities, expression pattern and modes of regulation. They play animportant role in numerous cell processes such as e.g. cell growth anddifferentiation processes, the control of cytoskeletal changes and theregulation of intracellular transport processes. On the basis of theirin vitro specificity for certain phosphoinositide substrates thePI3-kinases can be divided into different categories. The mammaliantarget of rapamycin (mTOR) is a serine/threonine kinase related to thelipide kinases of the PI3-kinase family. It exists in two complexes,mTORC1 and mTORC2, which are differentially regulated, have distinctsubstrate specificities, and are differentially sensitive to rapamycin.The central role of mTOR in controlling key cellular growth and survivalpathways has sparked interest in discovering mTOR inhibitors that bindto the ATP site and therefore target both mTORC2 and mTORC1. As aconsequence, inhibition of the PI3K pathway, particularly mediated viaPi3Kα and mTOR, has emerged as an attractive target for cancertherapeutics.

5-Alkynyl-pyrimidines are described for example as protein kinasesinhibiting compounds in WO2006044823.

DETAILED DESCRIPTION OF THE INVENTION

It has now surprisingly been found that compounds of general formula(1), wherein the groups R¹ to R⁴ have the meanings given below, act asinhibitors of kinases. In particular, the compounds of the inventioninhibit PI3Kα and mTOR kinases. Thus, the compounds according to theinvention may be used for example for the treatment of diseasesconnected with the activity of kinases and characterised by excessive orabnormal cell proliferation, like for example cancer.

The present invention relates to compounds of general formula (1)

wherein

R³ denotes a group selected from among 3-8 membered heterocycloalkyl,C₆₋₁₀aryl and 5-12 membered heteroaryl, optionally substituted by one ormore identical or different R⁴; and

R¹ denotes a group selected from among C₆₋₁₀aryl and 5-12 memberedheteroaryl, optionally substituted by one or more identical or differentR⁵ and

R² denotes a group selected from among hydrogen, C₁₋₄alkyl,C₃₋₈cycloalkyl, 3-8 membered heteroalkyl, 3-8 membered heterocycloalkyl,—OR^(v), —NR^(v)R^(v1), —SR^(v), —CF₃, —CN, —NC and —NO₂, and

each R⁴ denotes a group selected from among R^(a) and R^(b); and

each R^(a) independently of one another denotes hydrogen or a groupselected from among C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, R^(a)optionally being substituted by one or more identical or different R^(b)and/or R^(c4),

each R^(b) denotes a suitable group and is selected independently of oneanother from among ═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃, —OCHF₂, ═S,—SR^(c), ═NR^(c), ═NOR^(c), ═NNR^(c)R^(c1), ═NN(R^(g))C(O)NR^(c)R^(c1),—NR^(c)R^(c1), —ONR^(c)R^(c1), —N(OR^(c))R^(c1), —N(R^(g))NR^(c)R^(c1),halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(c),—S(O)OR^(c), —S(O)₂R^(c), —S(O)₂OR^(c), —S(O)NR^(c)R^(c1),—S(O)₂NR^(c)R^(c1), —OS(O)R^(c), —OS(O)₂R^(c), —OS(O)₂OR^(c),—OS(O)NR^(c)R^(c1), —OS(O)₂NR^(c)R^(c1), —C(O)R^(c), —C(O)OR^(c),—C(O)SR^(c), —C(O)NR^(c)R^(c1), —C(O)N(R^(g))NR^(c)R^(c1),—C(O)N(R^(g))OR^(c), —C(NR^(g))NR^(c)R^(c1), —C(NOH)R^(c),—C(NOH)NR^(c)R^(c1), —OC(O)R^(c), —OC(O)OR^(c), —OC(O)SR^(c),—OC(O)NR^(c)R^(c1), —OC(NR^(g))NR^(c)R^(c1), —SC(O)R^(c), —SC(O)OR^(c),—SC(O)NR^(c)R^(c1), —SC(NR^(g))NR^(c)R^(c1), —N(R^(g))C(O)R^(c),—N[C(O)R^(c)][C(O)R^(c1)], —N(OR^(g))C(O)R^(c),—N(R^(g))C(NR^(g1))R^(c), —N(R^(g))N(R^(g1))C(O)R^(c),—N[C(O)R₂]NR^(c)R^(c1), —N(R^(g))C(S)R^(c), —N(R^(g))S(O)R^(c),—N(R^(g))S(O)OR^(c), —N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)][S(O)₂R^(c1)],—N(R^(g))S(O)₂R^(c), —N(R^(g))S(O)₂NR^(c)R^(c1), —N(R^(g))[S(O)₂]₂R^(c),—N(R^(g))C(O)OR^(c), —N(R^(g))C(O)SR^(c), —N(R^(g))C(O)NR^(c)R^(c1),—N(R^(g))C(O)NR^(g1)NR^(c)R^(c1), —N(R^(g))N(R^(g1))C(O)NR^(c)R^(c1),—N(R^(g))C(S)NR^(c)R^(c1), —[N(R^(g))C(O)]₂R^(c), —N(R^(g))[C(O)]₂R^(c),—N{[C(O)]₂R^(c)}{[C(O)]₂R^(c)}, —N(R^(g))[C(O)]₂OR^(c),—N(R^(g))[C(O)]₂NR^(c)R^(c1), —N{[C(O)]₂OR^(c)}{[C(O)]₂OR^(c1)},—N{[C(O)]₂NR^(c)R^(c1)}{[C(O)]₂NR^(c2)R^(c3)}, —[N(R^(g))C(O)]₂OR^(c),—N(R^(g))C(NR^(g1))OR^(c), —N(R^(g))C(NOH)R^(c),—N(R^(g))C(NR^(g1))SR^(c), —N(R^(g))C(NR^(g1))NR^(c)R^(c1),—N(R^(g))C(═N—CN)NR^(c)R^(c1) and —N═C(R^(g))NR^(c)R^(c1) and

each R^(c), R^(c1), R^(c2), R^(c3) and R^(c4) independently of oneanother denotes hydrogen or a group selected from among C₁₋₆alkyl, 2-6membered heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 memberedhetero-aryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, R^(c), R^(c1),R^(c2), R^(c3) and R^(c4) independently optionally being substituted byone or more identical or different R^(d) and/or R^(c4), where Retogether with R^(g) and/or R^(c1) and/or R^(c2) and/or R^(c3) or R^(c2)together with R^(c3) may form a 3-8 membered heterocyclalkyl residue viaa shared C-, N-, O- or S-atom, and

each R^(d) denotes a suitable group and is selected independently of oneanother from among ═O, —OR^(e), C₁₋₃haloalkyloxy, —OCF₃, —OCHF2, ═S,—SR^(e), ═NR^(e), ═NOR^(e), ═NNR^(e)R^(e1), ═NN(R^(g2))C(O)NR^(e)R^(e1),—NR^(e)R^(e1), —ONR^(e)R^(e1), —N(R^(g2))NR^(e)R^(e1), halogen, —CF₃,—CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(e), —S(O)OR^(e),—S(O)₂R^(e), —S(O)₂OR^(e), —S(O)NR^(e)R^(e1), —S(O)₂NR^(e)R^(e1),—OS(O)R^(e), —OS(O)₂R^(e), —OS(O)₂OR^(e), —OS(O)NR^(e)R^(e1),—OS(O)₂NR^(e)R^(e1), —C(O)R^(e), —C(O)OR^(e), —C(O)SR^(e),—C(O)NR^(e)R^(e1), —C(O)N(R^(g2))NR^(e)R^(e1), —C(O)N(R^(g2))OR^(e),—C(NR^(g2))NR^(e)R^(e1), —C(NOH)R^(e), —C(NOH)NR^(e)R^(e1), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)SR^(e), —OC(O)NR^(e)R^(e1),—OC(NR^(g2))NR^(e)R^(e1), —SC(O)R^(e), —SC(O)OR^(e), —SC(O)NR^(e)R^(e1),—SC(NR^(g2))NR^(e)R^(e1), —N(R^(g2))C(O)R^(e),—N[C(O)R^(e)][C(O)R^(e1)], —N(OR^(g2))C(O)R^(e),—N(R^(g2))C(NR^(g3))R^(e), —N(R^(g2))N(R^(g3))C(O)R^(e),—N[C(O)R^(e2)]NR^(e)R^(e1), —N(R^(g2))C(S)R^(e), —N(R^(g2))S(O)R^(e),—N(R^(g2))S(O)OR^(e), —N(R^(g2))S(O)₂R^(e), —N[S(O)₂R^(e)][S(O)₂R^(e1)],—N(R^(g2))S(O)₂OR^(e), —N(R^(g2))S(O)₂NR^(e)R^(e1),—N(R^(g2))[S(O)₂]₂R^(e), —N(R^(g2))C(O)OR^(e), —N(R^(g2))C(O)SR^(e),—N(R^(g2))C(O)NR^(e)R^(e1), —N(R^(g2))C(O)NR^(g3)NR^(e)R^(e1),—N(R^(g2))N(R^(g3))C(O)NR^(e)R^(e1), —N(R^(g2))C(S)NR^(e)R^(e1),—[N(R^(g2))C(O)][N(R^(g3))C(O)]R^(e), —N(R^(g2))[C(O)]₂R^(e),—N{[C(O)]₂R^(e)}{[C(O)]₂R^(e1)}, —N(R^(g2))[C(O)]₂OR^(e),—N(R^(g2))[C(O)]₂NR^(e)R^(e1), —N{[C(O)]₂OR^(e)}{[C(O)]₂OR^(e)},—N{[C(O)]₂NR^(e)R^(e1)}{[C(O)]₂NR^(e2)R^(e3)},—[N(R^(g3))C(O)][N(R^(g3))C(O)]OR^(e), —N(R^(g2))C(NR^(g3))OR^(e),—N(R^(g2))C(NOH)R^(e), —N(R^(g2))C(NR^(g3))SR^(e),—N(R^(g2))C(NR^(g3))NR^(e)R^(e1), —N(R^(g2))C(═N—CN)NR^(e)R^(e1) and—N═C(R^(g2))NR^(e)R^(e1),

each R^(e), R^(e1), R^(e2), R^(e3) and R^(e4) independently of oneanother denotes hydrogen or a group selected from among C₁₋₆alkyl, 2-6membered heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 memberedhetero-aryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, where R^(e)together with R^(g2) and/or R^(e1) and/or R^(e2) and/or R^(e3) or R^(e2)together with R^(e3) may form a 3-8 membered heterocyclalkyl residue viaa shared C-, N-, O- or S-atom, and where R^(e), R^(e1), R^(e2), R^(e3)and R^(e4) independently optionally being substituted by one or moreidentical or different R^(f) and/or R^(g6), and

each R^(f) denotes a suitable group and in each case is selectedindependently of one another from among ═O, —OR^(g), C₁₋₃haloalkyloxy,—OCF₃, —OCHF₂, ═S, —SR^(g), ═NR^(g4), ═NOR^(g4), ═NNR^(g4)R^(g5),═NN(R^(h))C(O)NR^(g4)R^(g5), —NR^(g4)R^(g5), —ONR^(g4)R^(g5),—N(R^(h))NR^(g4)R^(g5), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(g4), —S(O)OR^(g4), —S(O)₂R^(g4), —S(O)₂OR^(g4),—S(O)NR^(g4)R^(g5), —S(O)₂NR^(g4)R^(g5), —OS(O)R^(g4), —OS(O)₂R^(g4),—OS(O)₂OR^(g4), —OS(O)NR^(g4)R^(g5), —OS(O)₂NR^(g4)R^(g5), —C(O)R^(g4),—C(O)OR^(g4), —C(O)SR^(g4), —C(O)NR^(g4)R^(g5),—C(O)N(R^(h))NR^(g4)R^(g5), —C(O)N(R^(h))OR^(g4),—C(NR^(h))NR^(g4)R^(g5), —C(NOH)R^(g4), —C(NOH)NR^(g4)R^(g5),—OC(O)R^(g4), —OC(O)OR^(g4), —OC(O)SR^(g4), —OC(O)NR^(g4)R^(g5),—OC(NR^(h))NR^(g4)R^(g5), —SC(O)R^(g4), —SC(O)OR^(g4),—SC(O)NR^(g4)R^(g5), —SC(NR^(h))NR^(g4)R^(g5), —N(R^(h))C(O)R^(g4),—N[C(O)R^(g4)]2, —N(OR^(h))C(O)R^(g4), —N(R^(h))C(NR^(h1))R^(g4),—N(R^(h))N(R^(h1))C(O)R^(g4), —N[C(O)R^(g6)]NR^(g4)R^(g5),—N(R^(h))C(S)R^(g4), —N(R^(h))S(O)R^(g4), —N(R^(h))S(O)OR^(g4),—N(R^(h))S(O)₂R^(g4), —N[S(O)₂R^(g4])[S(O)₂R^(g)], —N(R^(h))S(O)₂R^(g4),—N(R^(h))S(O)₂NR^(g4)R^(g5), —N(R^(h))[S(O)₂]₂R^(g4),—N(R^(h))C(O)OR^(g4), —N(R^(h))C(O)SR^(g4), —N(R^(h))C(O)NR^(g4)R^(g5),—N(R^(h))C(O)NR^(h1)NR^(g4)R^(g5), —N(R^(h))N(R^(h1))C(O)NR^(g4)R^(g5),—N(R^(h))C(S)NR^(g4)R^(g5), —[N(R^(h))C(O)][N(R^(h1))C(O)]R^(g4),—N(R^(h))[C(O)]₂R^(g4), —N{[C(O)]₂R^(g4)}{[C(O)]₂R⁵},—N(R^(h))[C(O)]₂OR^(g4), —N(R^(h))[C(O)]₂NR^(g4)R^(g5),—N{[C(O)]₂R^(g4)}{[C(O)]₂OR^(g4)},—N{[C(O)]₂NR^(g4)R^(g5)}{[C(O)]₂NR^(g4)R^(g5)},—[N(R^(h))C(O)][N(R^(h1))C(O)]OR^(g4), —N(R^(h))C(NR^(h1))OR^(g4),—N(R^(h))C(NOH)R^(g4), —N(R^(h))C(NR^(h1))SR^(g4),—N(R^(h))C(NR^(h1))NR^(g4)R^(g5), —N(R^(h))C(═N—CN)NR^(g4)R^(g5) and—N═C(R^(h))NR^(g4)R^(g5); and

each R^(g), R^(g1), R^(g2), R^(g3), R^(g4), R^(g5) and R^(g6)independently of one another denotes hydrogen or a group selected fromamong C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12membered hetero-aryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, where R^(g)together with R^(g1) and/or R^(h) may form a 3-8 membered cycloalkyl ora 3-8 membered heterocyclalkyl residue via a shared C-, N-, O- orS-atom, and where R^(g), R^(g1), R^(g2), R^(g3), R^(g4), R^(g5) andR^(g6) independently optionally being substituted by one or moreidentical or different R^(h2); and

each R^(h), R^(h1) and R^(h2) is selected independently of one anotherfrom among hydrogen, C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, where R^(h)together with R^(h1) may form a 3-8 membered cycloalkyl or a 3-8membered heterocyclalkyl residue via a shared C-, N-, O- or S-atom, and

each R⁵ denotes a group selected from among R^(m) and R^(n); and

each R^(m) independently of one another denotes hydrogen or a groupselected from among C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, and R^(m)optionally substituted by one or more identical or different R^(n)and/or R^(o4),

each R^(n) denotes a suitable group and is selected independently of oneanother from among ═O, —OR^(o), C₁₋₃haloalkyloxy, —OCF₃, —OCHF₂, ═S,—SR^(o), ═NR^(o), ═NOR^(o), ═NNR^(o)R^(o1), ═NN(R^(s))C(O)NR^(o)R^(o1),—NR^(o)R^(o1), —ONR^(o)R^(o1), —N(OR^(o))R^(o1), —N(R^(s))NR^(o)R^(o1),halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(o),—S(O)OR^(o), —S(O)₂R^(o), —S(O)₂OR^(o), —S(O)NR^(o)R^(o1),—S(O)₂NR^(o)R^(o1), —OS(O)R^(o), —OS(O)₂R^(o), —OS(O)₂OR^(o),—OS(O)NR^(o)R^(o1), —OS(O)₂NR^(o)R^(o1), —C(O)R^(o), —C(O)OR^(o),—C(O)SR^(o), —C(O)NR^(o)R^(o1), —C(O)N(R^(s))NR^(o)R^(o1),—C(O)N(R^(s))OR^(o), —C(NR^(s))NR^(o)R^(o1), —C(NOH)R^(o),—C(NOH)NR^(o)R^(o1), —OC(O)R^(o), —OC(O)OR^(o), —OC(O)SR^(o),—OC(O)NR^(o)R^(o1), —OC(NR^(s))NR^(o)R^(o1), —SC(O)R^(o), —SC(O)OR^(o),—SC(O)NR^(o)R^(o1), —SC(NR^(s))NR^(o)R^(o1), —N(R^(s))C(O)R^(o),—N[C(O)R^(o)][C(O)R^(o)], —N(OR^(s))C(O)R^(o), —N(R^(s))C(NR^(s1))R^(o),—N(R^(s))N(R^(s1))C(O)R^(o), —N[C(O)R^(o2)]NR^(o)R^(o1),—N(R^(s))C(S)R^(o), —N(R^(s))S(O)R^(o), —N(R^(s))S(O)OR^(o),—N(R^(s))S(O)₂R^(o), —N[S(O)₂R^(o)][S(O)₂R^(o1)], —N(R^(s))S(O)₂OR^(o),—N(R^(s))S(O)₂NR^(o)R^(o1), —N(R^(s))[S(O)₂]₂R^(o), —N(R^(s))C(O)OR^(o),—N(R^(s))C(O)SR^(o), —N(R^(s))C(O)NR^(o)R^(o1),—N(R^(s))C(O)NR^(s1)NR^(o)R^(o1), —N(R^(s))N(R^(s1))C(O)NR^(o)R^(o1),—N(R^(s))C(S)NR^(o)R^(o1), —[N(R^(s))C(O)]₂R^(o), —N(R^(s))[C(O)]₂R^(o),—N{[C(O)]₂R}{[C(O)]₂R^(o1)}, —N(R^(s))[C(O)]₂OR^(o),—N(R^(s))[C(O)]₂NR^(o)R^(o1), —N{[C(O)]₂OR^(o)}{[C(O)]₂OR^(o1)},—N{[C(O)]₂NR^(o)R^(o1)}{[C(O)]₂NR^(o2)R^(o3)}, —[N(R^(s))C(O)]₂OR^(o),—N(R^(s))C(NR^(s1))OR^(o), —N(R^(s))C(NOH)R^(o),—N(R^(s))C(NR^(s1))SR^(o), —N(R^(s))C(NR^(s1))NR^(o)R^(o1) and—N═C(R^(s))NR^(o)R^(o1) and each R^(o), R^(o1), R^(o2) and R^(o3)independently of one another denotes hydrogen or a group selected fromamong C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12membered hetero-aryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, where R^(o)together with R^(s) and/or R^(c1) and/or R^(c2) and/or R^(c3) or R^(c2)together with R^(c3) may form a 3-8 membered heterocyclalkyl residue viaa shared C-, N-, O- or S-atom, and where R^(o), R^(o1), R^(o2) andR^(o3) independently optionally being substituted by one or moreidentical or different R^(p) and/or R^(q4), and

each R^(p) denotes a suitable group and is selected independently of oneanother from among ═O, —OR^(q), C₁₋₃haloalkyloxy, —OCF₃, —OCHF₂, ═S,—SR^(q), ═NR^(q), ═NOR^(q), ═NNR^(q)R^(q1), ═NN(R^(s))C(O)NR^(q)R^(q1),—NR^(q)R^(q1), —ONR^(q)R^(q1), —N(R^(s))NR^(q)R^(q1), halogen, —CF₃,—CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(q), —S(O)OR^(q),—S(O)₂R^(q), —S(O)₂OR^(q), —S(O)NR^(q)R^(q1), —S(O)₂NR^(q)R^(q1),—OS(O)R^(q), —OS(O)₂R^(q), —OS(O)₂OR^(q), —OS(O)NR^(q)R^(q1),—OS(O)₂NR^(q)R^(q1), —C(O)R^(q), —C(O)OR^(q), —C(O)SR^(q),—C(O)NR^(q)R^(q1), —C(O)N(R^(s))NR^(q)R^(q1), —C(O)N(R^(s))OR^(q),—C(NR^(s))NR^(q)R^(q1), —C(NOH)R^(q), —C(NOH)NR^(q)R^(q1), —OC(O)R^(q),—OC(O)OR^(q), —OC(O)SR^(q), —OC(O)NR^(q)R^(q1), —OC(NR^(s))NR^(q)R^(q1),—SC(O)R^(q), —SC(O)OR^(q), —SC(O)NR^(q)R^(q1), —SC(NR^(s))NR^(q)R^(q1),—N(R^(s))C(O)R^(q), —N[C(O)R^(q)][C(O)R^(q)], —N(OR^(s))C(O)R^(q),—N(R^(s))C(R^(s1))R^(q), —N(R^(s))N(R^(s1))C(O)R^(q),—N[C(O)R^(q2)]NR^(q)R^(q1), —N(R^(s))C(S)R^(q), —N(R^(s))S(O)R^(q),—N(R^(s))S(O)OR^(q), —N(R^(s))S(O)₂R^(q), —N[S(O)₂R][S(O)₂R^(q1)],—N(R^(s))S(O)₂OR^(q), —N(R^(s))S(O)₂NR^(q)R^(q1),—N(R^(s))[S(O)₂]₂R^(q), —N(R^(s))C(O)OR^(q), —N(R^(s))C(O)SR^(q),—N(R^(s))C(O)NR^(q)R^(q1), —N(R^(s))C(O)NR^(s1)NR^(q)R^(q1),—N(R^(s))N(R^(s1))C(O)NR^(q)R^(q1), —N(R^(s))C(S)NR^(q),—[N(R^(s))C(O)][N(R^(g1))C(O)]R^(q), —N(R^(s))[C(O)]₂R^(q),—N{[C(O)]₂R^(q)}{[C(O)]₂R^(q1)}), —N(R^(s))[C(O)]₂OR^(q),—N(R^(s))[C(O)]₂NR^(q)R^(q1), —N{[C(O)]₂OR^(q)}{[C(O)]₂OR^(q1)},—N{[C(O)]₂NR^(q)R^(q1)}{[C(O)]₂NR^(q2)R^(q3)},—[N(R^(s))C(O)][N(R^(s1))C(O)]OR^(q), —N(R^(s))C(NR^(s1))OR^(q),—N(R^(s))C(NOH)R^(q), —N(R^(s))C(NR^(s1))SR^(q),—N(R^(s))C(NR^(s1))NR^(q)R^(q1), —N(R^(s))C(═N—CN)NR^(q)R^(q1) and—N═C(R^(s))NR^(q)R^(q1), and

each R^(q), R^(q1), R^(q2), R^(q3) and R^(q4) independently of oneanother denotes hydrogen or a group selected from among C₁₋₆alkyl, 2-6membered heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 memberedhetero-aryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, where R^(q)together with R^(q1) and/or R^(q2) and/or R^(q3) and/or R^(s) may form a3-8 membered heterocyclalkyl residue via a shared C-, N-, O- or S-atom,wherein R^(q), R^(q1), R^(q2), R^(q3) and R^(q4) are optionallyindependently substituted by one or more identical or different R^(r)and/or R^(s4), and

each R^(r) denotes a suitable group and in each case is selectedindependently of one another from among ═O, —OR^(s), C₁₋₃haloalkyloxy,—OCF₃, —OCHF₂, ═S, —SR^(s), ═NR^(s), ═NOR^(s), ═NNR^(s)R^(s1),═NN(R^(t))C(O)NR^(s)R^(s1), —NR^(s)R^(s1), —ONR^(s)R^(s1),—N(R^(h))NR^(s)R^(s1), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(s), —S(O)OR^(s), —S(O)₂R^(s), —S(O)₂OR^(s),—S(O)NR^(s)R^(s1), —S(O)₂NR^(s)R^(s1), —OS(O)R^(s), —OS(O)₂R^(s),—OS(O)₂OR^(s), —OS(O)NR^(s)R^(s1), —OS(O)₂NR^(s)R^(s1), —C(O)R^(s),—C(O)OR^(s), —C(O)SR^(s), —C(O)NR^(s)R^(s1), —C(O)N(R^(t))NR^(s)R^(s1),—C(O)N(R^(t))OR^(s), —C(NR^(t))NR^(s)R^(s1), —C(NOH)R^(s),—C(NOH)NR^(s)R^(s1), —OC(O)R^(s), —OC(O)OR^(s), —OC(O)SRS,—OC(O)NR^(s)R^(s1), —OC(NR^(t))NR^(s)R^(s1), —SC(O)R^(s), —SC(O)OR^(s),—SC(O)NR^(s)R^(s1), —SC(NR^(t))NR^(s)R^(s), —N(R^(t))C(O)R^(s),—N[C(O)R^(s)][C(O)R^(s1)], —N(OR^(t))C(O)R^(s),—N(R^(t))C(NR^(t1))R^(s), —N(R^(t))N(R^(t1))C(O)R^(s),—N[C(O)R^(g2)]NR^(s)R^(s1), —N(R^(t))C(S)R^(s), —N(R^(t))S(O)R^(s),—N(R^(t))S(O)OR^(s), —N(R^(t))S(O)₂R^(s), —N[S(O)₂R^(s)][S(O)₂R^(s1)],—N(R^(t))S(O)₂OR^(s), —N(R^(t))S(O)₂NR^(s)R^(s1),—N(R^(t))[S(O)₂]₂R^(s), —N(R^(t))C(O)OR^(s), —N(R^(t))C(O)SR^(s),—N(R^(t))C(O)NR^(s)R^(s1), —N(R^(t))C(O)NR^(t1)NR^(s)R^(s1),—N(R^(t))N(R^(t1))C(O)NR^(s)R^(s1), —N(R^(t))C(S)NR^(s)R^(s1),—[N(R^(t))C(O)][N(R^(h1))C(O)]R^(s), —N(R^(t))[C(O)]₂R^(s),—N{[C(O)]₂R^(s)}{[C(O)]₂R^(s1)}, —N(R^(t))[C(O)]₂OR^(s),—N(R^(t))[C(O)]₂NR^(s)R^(s1), —N{[C(O)]₂OR^(s)}{[C(O)]₂OR^(s1)},—N{[C(O)]₂NR^(s)R^(s1)}{[C(O)]₂NR^(s2)R^(s3)},—[N(R^(t))C(O)][N(R^(t1))C(O)]OR, —N(R^(t))C(NR^(t1))OR^(s),—N(R^(t))C(NOH)R^(s), —N(R^(t))C(NR^(t1))SR^(s),—N(R^(t))C(NR^(t1))NR^(s)R^(s1); and —N═C(R^(t))NR^(s)R^(s1); and

each R^(s), R^(s1), R^(s2), R^(s3) and R^(s4) independently of oneanother denotes hydrogen or a group selected from among C₁₋₆alkyl, 2-6membered heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 memberedhetero-aryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, where R^(s)together with R^(s1) and/or R^(s2) and/or R^(s3) and/or R^(t) may form a3-8 membered heterocyclalkyl residue via a shared C-, N-, O- or S-atom,R^(s), R^(s1), R^(s2), R^(s3) and R^(s4) independently optionally beingsubstituted by one or more identical or different R^(t2); and eachR^(t), R^(t1) and R^(t2) is selected independently of one another fromamong hydrogen, C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, where R^(t)together with R^(t1) may form a 3-8 membered heterocyclalkyl residue viaa shared C-, N-, O- or S-atom, and

each R^(v) and R^(v1) is selected independently of one another fromamong hydrogen, C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,where R^(v) together with R^(v1) may form a 3-8 membered heterocyclalkylresidue via a shared C-, N-, O- or S-atom,

optionally in the form of the prodrugs, the tautomers, the racemates,the enantiomers, the diastereomers, the prodrugs and the mixturesthereof, and optionally the pharmacologically acceptable salts thereof.

In a preferred embodiment R² denotes a group selected from amongC₃₋₈cycloalkyl, 3-8 membered heteroalkyl, 3-8 membered heterocycloalkyl,—OR^(v), —NR^(v)R^(v1), —CF₃, —CN, —NC and —NO₂.

In another preferred embodiment R² denotes —C₁₋₄-alkyl.

In another preferred embodiment R² denotes —CH₃ or —C₂H₅.

In another preferred embodiment R¹ denotes phenyl or pyridyl, optionallysubstituted by one or more identical or different R⁵.

In another preferred embodiment R⁵ denotes a group selected from amongR^(m), R^(n); and each R^(m) independently of one another denoteshydrogen or a group selected from among C₁₋₄alkyl, C₄₋₆cycloalkyl,methoxyethyl, cyclopropylmethyl, phenyl, naphthyl, benzyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl, wherein R^(m) is optionallyindependently substituted by one or more identical or different R^(n)and/or R^(o4), and

each R^(n) denotes a suitable group and is selected independently of oneanother from among ═O, —OH, —OCH₃, —OC₂H₅, —OCF₃, —OCHF₂, —SCH₃, ═NOH,═NOCH₃, —NR^(o)R^(o1), —F, —Cl, —Br, —CF₃, —CN, —NO₂, —N₃, —S(O)R^(o),—S(O)₂R^(o), —C(O)R^(o), —C(O)OR^(o), —C(O)NR^(o)R^(o1), —OC(O)R^(o),—OC(O)OR^(o), —OC(O)NR^(o)R^(o1), —N(R^(s))C(O)R^(o),—N(R^(s))S(O)R^(o), —N(R^(s))S(O)₂R^(o), —N(R^(s))S(O)₂NR^(o)R^(o1),—N(R^(s))C(O)OR^(o), —N(R^(s))C(O)NR^(o)R^(o1), and

each R^(o), R^(o1) and R^(o4) independently of one another denoteshydrogen or a group selected from among C₁₋₄alkyl, 2-6 memberedheteroalkyl, C₃₋₆cycloalkyl, C₄₋₁₀cycloalkylalkyl, phenyl, benzyl, 5-6membered heteroaryl, C₄₋₆heterocycloalkyl, where R^(o) together withR^(o1) or R^(s) may form a 3-8 membered heterocyclalkyl residue via ashared C-, N-, O- or S-atom, wherein R^(o), R^(o1) and R^(o4) isoptionally independently substituted by one or more identical ordifferent R^(P) and/or R^(q4), and

each R^(P) denotes a suitable group and is selected independently of oneanother from among ═O, —OH, methoxy, ethoxy, isopropoxy, —OCF₃, —OCHF₂,—SCH₃, amino, methylamino, dimethylamino, ethylamino, isopropylamino,morpholine, piperidine, pyrrolidine, piperazine, N-methylpiperazine,acetyl, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl,methoxycarbonyl, ethoxycarbonyl, —F, —Cl, —Br, —CF₃, —CN, —S(O)₂C₂H₅,—S(O)₂CH₃, and

each R^(q4) denotes a suitable group and is independently of one anotherselected from among C₁₋₄alkyl, 4-6 membered heteroalkyl, C₄₋₆cycloalkyl,C₄₋₇cycloalkylalkyl, phenyl, benzyl, 5-6 membered heteroaryl, 6-8membered heteroarylalkyl, 4-6 membered heterocycloalkyl and 4-7 memberedheterocycloalkylalkyl, and

each R^(s) independently of one another denotes hydrogen or a groupselected from among C₁₋₄alkyl, 2-6 membered heteroalkyl, C₃₋₈cycloalkyl,C₄₋₁₀cycloalkylalkyl, phenyl, benzyl, 5-6 membered heteroaryl, 6-12membered heteroarylalkyl, 3-8 membered heterocycloalkyl and 4-10membered heterocycloalkylalkyl.

In another preferred embodiment R^(q4) denotes a suitable group and isindependently of one another selected from among methyl, ethyl,1-propyl, 2-propyl, 1-butyl, tert-butyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropylmethyl, methoxyethyl, phenyl, benzyl, pyridyl, pyrimidinyl,pyridazinyl, imidazolyl, pyrazolyl, thiazolyl.

In another preferred embodiment R⁵ denotes a group selected from amongR^(n), and each R^(n) denotes a suitable group and is selectedindependently of one another from among methoxy, ethoxy, —F, —Cl,—C(O)R^(o), —C(O)NR^(o)R^(o1), and

each R^(o) and R^(o1) independently of one another denotes hydrogen or agroup selected from among methyl, ethyl, prop-2-yl, prop-1-yl,methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropylmethyl, morpholine, piperidine, pyrolidine, piperazine, orwhere R^(o) and R^(o1) form a cyclic amine, selected from morpholine,piperazine, homomorpholine, homopiperazine, piperidine, pyrolidine,wherein R^(o) and R^(o1) are independently optionally substituted by oneor more identical or different R^(p) and/or R^(q4), and each R^(p)denotes a suitable group and is selected independently of one anotherfrom among ═O, —OH, methoxy, ethoxy, isopropoxy, amino, methylamino,dimethylamino, ethylamino, isopropylamino, acetyl, methylsulfonyl,ethylsulfonyl, isopropylsulfonyl, methoxycarbonyl, ethoxycarbonyl, —F,—Cl, —Br, —CF₃, —CN, and

each R^(q4) denotes a suitable group and is independently of one anotherselected from among methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl,tert-butyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl,N-methylpiperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiophenyl, 1,1-dioxo-tetrahydrothiophenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, methoxyethyl,phenyl, benzyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl,pyrazolyl, thiazolyl.

In another preferred embodiment R¹ denotes pyridyl, and wherein R⁵ andR⁵ are selected from among methyl, ethyl, n-propyl, isopropyl,cyclopropyl, methoxy, —CF₃.

In another preferred embodiment R¹ denotes phenyl, and wherein R⁵wherein R⁵ are selected from among R^(n), and

each R^(n) denotes a suitable group and is selected independently of oneanother from among methyl, methoxy, ethoxy, —F, —Cl, —C(O)R^(o),—C(O)NR^(o)R^(o1), and

each R^(o) and R^(o1) independently of one another denotes hydrogen or agroup optionally substituted by one or more identical or different R^(p)and/or R^(q4), selected from among methyl, ethyl, prop-2-yl, prop-1-yl,methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropylmethyl, morpholine, piperidine, pyrolidine, piperazine, orwhere R^(o) and R^(o1) form a cyclic amine, selected from morpholine,piperazine, homomorpholine, homopiperazine, piperidine, pyrolidine,optionally substituted by one or more identical or different R^(p)and/or R^(q4), and

each R^(p) denotes a suitable group and is selected independently of oneanother from among ═O, —OH, methoxy, ethoxy, isopropoxy, amino,methylamino, dimethylamino, ethylamino, isopropylamino, acetyl,methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, methoxycarbonyl,ethoxycarbonyl, —F, —Cl, —Br, —CF₃, —CN, and

each R^(q4) denotes a suitable group and is independently of one anotherselected from among methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl,tert-butyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl,N-methylpiperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiophenyl, 1,1-dioxo-tetrahydrothiophenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, methoxyethyl,phenyl, benzyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl,pyrazolyl, thiazolyl.

In another preferred embodiment R³ denotes phenyl or pyridyl, optionallysubstituted by one or more identical or different R⁴.

In another preferred embodiment R⁴ denotes a group selected from amongR^(a), R^(b) and R^(a) substituted by one or more identical or differentR^(b) and/or R^(c); and

each R^(a) independently of one another is selected from among hydrogen,methyl, ethyl, and each R^(b) denotes a suitable group and is selectedindependently of one another from among —OCH₃, —NH₂, —NHCH₃, —NHC₂H₅,—F, —Cl, —Br, —CF₃, —CN.

In another preferred embodiment R³ denotes pyridyl, optionallysubstituted by one or more identical or different R⁴.

In another preferred embodiment R³ denotes pyridyl and wherein R⁴ and R⁴are selected from among methyl, ethyl, amino, methylamino, ethylamino.The compounds, or the pharmacologically effective salts thereof,according to the present invention can be used as medicaments.

The compounds, or the pharmacologically effective salts thereof,according to the present invention can be used for preparing amedicament with an antiproliferative activity.

The present invention also relates to pharmaceutical preparations,containing as active substance one or more compounds of general formula(1) according to the present invention or the pharmacologicallyeffective salts thereof, optionally in combination with conventionalexcipients and/or carriers.

The present invention also relates to compounds according to formula (1)for use in the treatment and/or prevention of cancer, infections,inflammatory and autoimmune diseases.

The present invention also relates to the use of compounds of generalformula (1) according to the present invention for preparing amedicament for the treatment and/or prevention of cancer, infections,inflammatory and autoimmune diseases.

The present invention also relates to pharmaceutical preparationcomprising a compound of general formula (1) according to the presentinvention and at least one other cytostatic or cytotoxic activesubstance, different from formula (1), optionally in the form of thetautomers, the racemates, the enantiomers, the diastereomers and themixtures thereof, as well as optionally the pharmacologically acceptablesalts thereof.

DEFINITIONS

As used herein the following definitions apply, unless stated otherwise.

By alkyl substituents are meant in each case saturated, unsaturated,straight-chain or branched aliphatic hydrocarbon groups (alkyl group)and this includes both saturated alkyl groups and unsaturated alkenyland alkynyl groups. Alkenyl substituents are in each case straight-chainor branched, unsaturated alkyl groups, which have at least one doublebond.

By alkynyl substituents are meant in each case straight-chain orbranched, unsaturated alkyl groups, which have at least one triple bond.

The term heteroalkyl refers to groups which can be derived from alkyl asdefined above in its broadest sense by replacing one or more of thegroups —CH₃ in the hydrocarbon chains independently of one another bythe groups —OH, —SH or —NH₂, one or more of the groups —CH₂—independently of one another by the groups —O—, —S— or —NH—, one or moreof the groups

by the group

one or more of the groups ═CH— by the group ═N—, one or more of thegroups ═CH₂ by the group ═NH or one or more of the groups ≡CH by thegroup ≡N, while in all only a maximum of three heteroatoms may bepresent in a heteroalkyl, there must be at least one carbon atom betweentwo oxygen and between two sulphur atoms or between one oxygen and onesulphur atom and the group as a whole must have chemical stability.

It flows from the indirect definition/derivation from alkyl thatheteroalkyl is made up of the sub-groups of saturated hydrocarbon chainswith hetero-atom(s), heteroalkenyl and heteroalkynyl, while furthersubdivision into straight-chain (unbranched) and branched may be carriedout. If a heteroalkyl is supposed to be substituted, the substitutionmay take place independently of one another, in each case mono- orpolysubstituted, at all the hydrogen-carrying oxygen, sulphur, nitrogenand/or carbon atoms. Heteroalkyl itself may be linked to the molecule assubstituent both through a carbon atom and through a heteroatom.

By way of example, the following representative compounds are listed:dimethylaminomethyl; dimethylaminoethyl (1-dimethylaminoethyl;2-dimethyl-aminoethyl); dimethylaminopropyl (1-dimethylaminopropyl,2-dimethylaminopropyl, 3-dimethylaminopropyl); diethylaminomethyl;diethylaminoethyl (1-diethylaminoethyl, 2-diethylaminoethyl);diethylaminopropyl (1-diethylaminopropyl, 2-diethylamino-propyl,3-diethylaminopropyl); diisopropylaminoethyl (1-diisopropylaminoethyl,2-di-isopropylaminoethyl); bis-2-methoxyethylamino;[2-(dimethylamino-ethyl)-ethyl-amino]-methyl;3-[2-(dimethylamino-ethyl)-ethyl-amino]-propyl; hydroxymethyl;2-hydroxy-ethyl; 3-hydroxypropyl; methoxy; ethoxy; propoxy;methoxymethyl; 2-methoxyethyl etc.

Haloalkyl relates to alkyl groups, wherein one or more hydrogen atomsare replaced by halogen atoms. Haloalkyl includes both saturated alkylgroups and unsaturated alkenyl and alkynyl groups, such as for example—CF₃, —CHF₂, —CH₂F, —CF₂CF₃, —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃,—CF₂CF₂CF₃, —CF₂CH₂CH₃, —CF═CF₂, —CCl═CH₂, —CBr═CH₂, —CI═CH₂, —C≡C—CF₃,—CHFCH₂CH₃ and —CHFCH₂CF₃.

Halogen refers to fluorine, chlorine, bromine and/or iodine atoms.

C₁₋₃haloalkoxy is meant to be C₁₋₃haloalkyl-O—.

By cycloalkyl is meant a mono, bicyclic or spirocyclic ring, while thering system may be a saturated ring or, however, an unsaturated,non-aromatic ring, which may optionally also contain double bonds, suchas for example cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl andnorbornenyl.

Cycloalkylalkyl includes a non-cyclic alkyl group wherein a hydrogenatom bound to a carbon atom, usually to a terminal C atom, is replacedby a cycloalkyl group.

Aryl relates to monocyclic or bicyclic aromatic rings with 6-10 carbonatoms such as phenyl and naphthyl, for example.

Arylalkyl includes a non-cyclic alkyl group wherein a hydrogen atombound to a carbon atom, usually to a terminal C atom, is replaced by anaryl group.

By heteroaryl are meant mono- or bicyclic aromatic rings, which insteadof one or more carbon atoms contain one or more, identical or differenthetero atoms, such as e.g. nitrogen, sulphur or oxygen atoms. Examplesinclude furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl,thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl.Examples of bicyclic heteroaryl groups are indolyl, isoindolyl,benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolyl, benzopyrazolyl, indazolyl,isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl,quinazolinyl and benzotriazinyl, indolizinyl, oxazolopyridyl,imidazopyridyl, naphthyridinyl, indolinyl, isochromanyl, chromanyl,tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuryl,isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridyl,benzotetrahydrofuryl, benzotetrahydrothienyl, purinyl, benzodioxolyl,triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl,imidazopyridyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl,benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridyl-N-oxidetetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl-N-oxide,pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide,quinolinyl-N-oxide, indolyl-N-oxide, indolinyl-N-oxide,isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide,phthalazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide,oxazolyl-N-oxide, thiazolyl-N-oxide, indolizinyl-N-oxide,indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide,pyrrolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide,triazolyl-N-oxide, tetrazolyl-N-oxide, benzothiopyranyl-S-oxide andbenzothiopyranyl-S, S-dioxide.

Heteroarylalkyl encompasses a non-cyclic alkyl group wherein a hydrogenatom bound to a carbon atom, usually to a terminal C atom, is replacedby a heteroaryl group.

Heterocycloalkyl relates to saturated or unsaturated, non-aromaticmono-, bicyclic, spirocyclic or bridged bicyclic rings comprising 3-14carbon atoms, which instead of one or more carbon atoms carryheteroatoms, such as nitrogen, oxygen or sulphur. Examples of suchheterocyloalkyl groups are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl,piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl,homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl,thiomorpholinyl-S-oxide, thiomorpholinyl-S, S-dioxide,tetrahydropyranyl, tetrahydrothienyl, homothiomorpholinyl-S, S-dioxide,oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl,dihydropyridyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl-S-oxide, tetrahydrothienyl-S, S-dioxide,homothiomorpholinyl-S-oxide, 2-oxa-5-azabicyclo[2,2,1]heptane,8-oxa-3-aza-bicyclo[3.2.1]octane, 3.8-diaza-bicyclo[3.2.1]octane,2,5-diaza-bicyclo[2.2.1]heptane, 3.8-diaza-bicyclo[3.2.1]octane,3.9-diaza-bicyclo[4.2.1]nonane and 2.6-diaza-bicyclo[3.2.2]nonane,3,9-diaza-spiro[5.5]undecane, 2,9-diaza-spiro[5.5]undecane,2,8-diaza-spiro[4.5]decane, 1,8-diaza-spiro[4.5]decane,3-aza-spiro[5.5]undecane, 1,5-dioxa-9-aza-spiro[5.5]undecane,2-oxa-9-aza-spiro[5.5]undecane, 3-oxa-9-aza-spiro[5.5]undecane,8-aza-spiro[4.5]decane, 2-oxa-8-aza-spiro[4.5]decane,1,4-dioxa-8-aza-spiro[4.5]decane, 3-aza-spiro[5.6]dodecane,3,9-diaza-spiro[5.6]dodecane, 9-oxa-3-aza-spiro[5.6]dodecane and1,3,8-triaza-spiro[4.5]decane.

Heterocycloalkylalkyl relates to a non-cyclic alkyl group wherein ahydrogen atom bound to a carbon atom, usually to a terminal C atom, isreplaced by a heterocycloalkyl group.

The following Examples illustrate the present invention withoutrestricting its scope.

General Procedure 1 (GP1): Iodination of Pyrimidines or Pyridines

A solution of the pyrimidine or pyridine (1.0 eq.) in acetic acid iscooled to 0° C. and NIS (1.0 eq.) is added in one portion. The reactionmixture is stirred at RT until conversion of the starting material iscompleted (2-6 h). The mixture is poured on ice-cooled water and treatedwith a mixture of 5% Na₂S₂O₃ and 10% NaHCO₃. The precipitate is filteredoff, intensely washed with water and dried under vacuum at 40° C. Thecrude product can be used without further purification or is furtherpurified by chromatography on silica gel using a CH₂Cl₂/MeOH gradient.

General Procedure 2 (GP2): Sonogashira Reaction Method 1:

The halide (1.0 eq.) is dissolved in DMF or THF and 0.1 eq. Pd-catalyst(e.g. PdCl₂(PPh₃)₂ or Pd(PPh₃)₄) and CuI (0.1 eq.) are added.Subsequently, triethylamine (10.0 eq.) and finally the alkyne (1.5 eq.)are added and the reaction mixture is stirred at 65° C. The reaction ismonitored by LC-MS. If the iodide is not completed converted after 4 h,additional amounts of alkyne are added in small portions. The producteither precipitates from the reaction mixture (and is filtered off andif necessary re-crystallized) and/or, after removal of the solvent, ispurified by preparative RP-HPLC or chromatography on slica gel.

Method 2:

The halide (1.0 eq.) is dissolved in DMSO and Pd(PPh₃)₄ (0.1 eq.) andCuI (0.1 eq.) are added. Subsequently, diisopropylamine (0.9 eq.) andfinally the alkyne (1.2 eq.) are added. The reaction mixture is put on apre-heated hot plate and stirred at 80° C. The reaction is monitored byLC-MS. If the halide is not completed converted after 4 h, additionalamounts of alkyne are added in small portions. The product eitherprecipitates from the reaction mixture (and is filtered off and ifnecessary re-crystallized) and/or, after removal of the solvent, ispurified by preparative RP-HPLC or flash chromatography on slica gel.

General Procedure 3 (GP3): Desilylation of Alkynes

The TMS-alkyne (1.0 eq.) is dissolved in MeOH, K₂CO₃ (0.5 eq.) is addedin one portion and the reaction mixture is stirred at RT untilconversion is complete (3-16 h). The solvent is removed in vaccuo, thecrude product is dissolved in ethyl acetate and the organic phase isextracted with water. The organic phase is dried, filtered off and thesolvent removed in vaccuo. The product is either used without furtherpurification or purified by chromatography on silica gel using aDCM/MeOH or (cyclo-)hexane/ethyl acetate.

General Procedure 4 (GP4): Suzuki Coupling

The 4-chloropyrimidine (1.0 eq.) is dissolved in DME/water (20:1 v/v),boronic acid (1.3 eq.), K₂CO₃ (2.0 eq.) and Pd(PPh₃)₄ (0.2 eq.) areadded and the reaction mixture is stirred for 4 h under reflux. In casethe conversion of the starting material is not complete, additionalamounts of boronic acid and Pd-catalyst are added and the reaction isrun over night under reflux. After cooling to RT water is added. Theprecipitate is filtered off. In cases where the product is notprecipitated it is extracted with diethylether, the organic phase isdried, filtered off, and the solvent removed under reduced pressure. Theobtained product can either be used without further purification or ispurified by chromatography.

General Procedure 8 (GP8): Saponification of Esters

The ester is taken up in either THF or dioxane, 1.1-1.5 eq. of 1 N NaOHare added and the mixture is heated under reflux until reaction controlshows complete conversion of the starting material. The product eitherprecipitates from the reaction mixture and is used without additionalpurification steps or can further be purified by chromatography.

General Procedure 9 (GP9): Amide Formation with Amines

A mixture of 0.21 mmol starting material, 0.31 mmol TBTU or HATU and0.42 mmol Huenig's base in 2 mL DMSO is stirred for 5 min. Subsequently0.31 mmol of amine is added and the resultant mixture is stirred at RTover night. Purification is performed via preparative RP-HPLC yieldingafter evaporation of the solvent the desired product.

General Procedure 10 (GP10) Amide Formation with Acid Chlorides

To a mixture of 0.13 mmol of starting material and 67 μL Huenig's basein 2 mL THF is added 0.26 mmol acid chloride. The reaction mixture isstirred over night at RT. The solvent is evaporated and the residue istaken up in 1 mL DMSO. Insoluble material is filtered off and theresulting solution is purified via preparative RP-HPLC yielding afterevaporation of the solvent the desired product.

General Procedure 11 (GP11): Urea Formation with Isocyanates

To a mixture of 0.16 mmol of starting material and 64.4 μL Huenig's basein 2 mL THF is added 0.49 mmol isocyanate. The reaction mixture isstirred over night at RT. The solvent is evaporated and the residue istaken up in 1 mL DMSO. Insoluble material is filtered off and theresulting solution is purified via preparative RP-HPLC yielding afterevaporation of the solvent the desired product.

General Procedure 12 (GP12): Urea Formation via Pre-activation of theAmine.

A mixture of 0.34 mmol amine and 0.34 mmol N,N′-carbonyldiimidazole and0.34 mmol 1,8-diazabicyclo[5.4.0]undec-7-ene is stirred for 10 min atRT. Then 0.32 mmol of starting material is added in one portion. Thereaction mixture is heated at 100° C. for 1 h in the microwave. Thesolvent is evaporated and the residue is taken up in 1 mL DMSO.Insoluble material is filtered off and the resulting solution ispurified via preparative RP-HPLC yielding the desired product.

General Procedure 13 (GP13): Amide formation with carbonic acids

A mixture of 0.62 mmol carbonic acid, 0.93 mmol TBTU and 1.2 mmolHuenig's base in 2 mL DMSO is stirred for 5 min. Subsequently 0.31 mmolof starting material is added and the resultant mixture is stirred at RTover night. Purification is performed via preparative RP-HPLC yieldingafter evaporation of the solvent the desired product.

Intermediates A A-1a) 6-Methyl-3H-pyrimidin-4-one

100 g (0.70 mol) 4-Hydroxy-2-mercapto-6-methyl pyrimidine and 300 gRaney-Nickel are suspended in water (1000 mL) and the suspension isheated and stirred under reflux over night. Full conversion is detectedby TLC (10% MeOH in DCM). The catalyst is filtered off over celite andthe filtrate is evaporated to give crude product as a pale green solid.The product is used without further purification for the next step.

A-1b) 5-Iodo-6-methyl-3H-pyrimidin-4-one

To a stirred solution of 70 g (0.64 mol) 4-hydroxy-6-methyl pyrimidinein acetic acid is added 127 g (0.56 mol) NIS portion wise at RT within15 min. The reaction is stirred for 30 h at RT until all startingmaterial is consumed. The reaction mixture is diluted with water and thesolid product is filtered off and washed with sodium thiosulfatesolution to remove excess iodine. After drying, the desired product isobtained as a pale brown solid (90 g; 60%) which is used without furtherpurification.

A-1) 4-Chloro-5-iodo-6-methyl-pyrimidin

A suspension of 90 g (0.38 mol) 4-hydroxy-5-iodo-6-methyl pyrimidine in600 mL POCl₃ is heated for 1 h at 90° C. The reaction mixture isconcentrated under reduced pressure and the residue is poured intocrushed ice. The precipitated solid is collected by filtration andwashed with water. After drying, the desired product is obtained as asolid (90 g; 93%).

A-2a) 6-Ethyl-3H-pyrimidin-4-one

90 g (0.58 mol) 4-Hydroxy-2-mercapto-6-ethyl pyrimidine and 270 gRaney-Nickel are suspended in water (1000 mL). The suspension is heatedand stirred under reflux over night. Full conversion is detected by TLC(10% MeOH in DCM). The catalyst is filtered off over celite and thefiltrate is evaporated to give crude product as a pale green solid (70.0g; 98%). The product is used without further purification for the nextstep.

A-2b) 6-Ethyl-5-iodo-3H-pyrimidin-4-one

To a stirred solution of 70 g (0.56 mol) 4-hydroxy-6-ethyl pyrimidine inacetic acid is added 127 g (0.56 mol) NIS portion wise at RT within 15min. The reaction is stirred for 30 h at RT until all starting materialis consumed. The reaction mixture is diluted with water and the solidproduct is filtered off and washed with sodium thiosulfate solution toremove excess iodine. After drying, the desired product is obtained as asolid (90 g; 64%) which is used without further purification.

A-2c) 4-Chloro-5-iodo-6-ethyl-pyrimidin

A suspension of 90 g (0.36 mol) 4-hydroxy-5-iodo-6-ethyl pyrimidine in600 mL POCl₃ is heated for 1 h at 90° C. The reaction mixture isconcentrated under reduced pressure and the residue is poured intocrushed ice. The precipitated solid is collected by filtration andwashed with water. After drying, the desired product is obtained as asolid (65 g; 67%).

A-2) 5-Iodo-3-trifluoromethyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP1starting from 5.0 g (31 mmol) 3-trifluoro-pyridin-2-ylamine and 6.9 g(31 mmol) NIS. Yield after precipitation from the reaction mixture: 6.78g (76%).

A-3) 6-Trifluoromethyl-5-iodo-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP1starting from 4.8 g (30 mmol) 6-trifluoromethyl-pyridin-2ylamine and 6.7g (30 mmol) NIS. Yield after precipitation from the reaction mixture andisolation of additional product from the mother liquid by chromatographyin silica gel: 5.73 g (67%).

A-4) 5-Iodo-6-methyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP1starting from 2.7 g (25 mmol) 6-methyl-pyridin-2-ylamine and 5.6 g (25mmol) NIS. Small amounts of the corresponding bis-iodopyridine areformed during the reaction (LC-MS). The reaction mixture is poured intoice upon which the bis-iodo product precipitated. The mother liquid istreated with a mixture of 5% Na₂S₂O₃ and 10% NaHCO₃ and is subsequentlyneutralized by addition of 4 N NaOH. The precipitated product iscollected by filtration and washed with water. Yield: 4.95 g (85%).

A-5) 6-Ethyl-5-iodo-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP1starting from 10.0 g (83 mmol) 6-ethyl-pyridin-2-ylamine and 18.4 g (83mmol) NIS. Yield after precipitation from the reaction mixture: 18.0 g(89%).

A-6) 5-Iodo-4-methyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP1starting from 2.0 g (18 mmol) 4-methyl-pyridin-2-ylamine and 4.2 g (18mmol) NIS. Yield after precipitation from the reaction mixture: 3.6 g(83%).

A-7) 4-Ethyl-5-iodo-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP1starting from 5.0 g (41 mmol) 4-ethyl-pyridin-2-ylamine and 9.2 g (41mmol) NIS. Yield after precipitation from the reaction mixture andisolation of additional product from the mother liquid by chromatographyusing silica gel: 10.3 g (100%).

A-8) 4-Trifluoromethyl-5-iodo-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP1starting from 20.0 g (123 mmol) 4-trifluoromethyl-pyridin-2-ylamine and27.8 g (123 mmol) NIS. Yield after precipitation from the reactionmixture and isolation of additional product from the mother liquid bychromatography in silica gel: 20.3 g (57%).

A-9) 3-Fluoro-5-iodo-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP1starting from 200 mg (1.78 mmol) 3-fluoro-pyridin-2ylamine and 401 mg(1.78 mmol) NIS. Yield after precipitation from the reaction mixture:380 mg (90%).

A-10) 2-Methyl-5-trimethylsilanylethynyl-pyridine

The title compound is synthesized according to general procedure GP2starting from 2.0 g (11.6 mmol) 5-bromo-pyridin-2-ylamine and 2.3 mL(16.3 mmol) 1-trimethylsilyl-ethyne using 68 mg (0.36 mmol) CuI, 305 mg(1.2 mmol) triphenylphosphine, 213 mg (0.30 mmol) PdCl₂(PPh₃)₂ and 18 mL(127 mmol) triethylamine in 18 mL dry THF. For the work-up the reactionmixture is diluted with ethyl acetate, the organic phase is extractedwith water and brine. The product is purified by chromatography onsilica gel using a hexane/ethyl acetate gradient. Yield: 1.5 g (68%).

A-11) 5-Trimethylsilanylethynyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP2starting from 5.0 g (28.9 mmol) 5-bromo-pyridin-2-ylamine and 5.7 mL(40.5 mmol) 1-trimethylsilyl-ethyne using 168 mg (0.88 mmol) CuI, 758 mg(2.9 mmol) triphenylphosphine, 533 mg (0.76 mmol) PdCl₂(PPh₃)₂ and 40 mL(288 mmol) triethylamine in 40 mL dry THF. For the work-up the reactionmixture is diluted with ethyl acetate and small amounts of cyclohexane,the organic phase is extracted with water and brine. The product ispurified by chromatography on silica gel using hexane/ethyl acetate(10/1 v/v). Yield: 5.0 g (91%). A-12)Methyl-(5-trimethylsilanylethynyl-pyridin-2-yl)-amine

The title compound is synthesized according to general procedure GP2starting from 4.3 g (23.0 mmol) 5-bromo-2-methylamino-pyridine and 4.5mL (32.2 mmol) 1-trimethylsilyl-ethyne using 134 mg (0.71 mmol) CuI, 601mg (2.3 mmol) triphenylphosphine, 420 mg (0.60 mmol) PdCl₂(PPh₃)₂ and 32mL (101 mmol) triethylamine in 40 mL dry THF. For the work-up thereaction mixture is diluted with ethyl acetate and small amounts ofcyclohexane, the organic phase is extracted with water and brine. Theproduct is purified by chromatography on silica gel using a hexane/ethylacetate gradient. Yield: 4.0 g (85%).

A-13) Ethyl-(5-trimethylsilanylethynyl-pyridin-2-yl)-amine

The title compound is synthesized according to general procedure GP2starting from 909 mg (4.5 mmol) 5-bromo-2-ethylamino-pyridine and 0.89mL (6.3 mmol) 1-trimethyl-silyl-ethyne using 26 mg (0.13 mmol) CuI, 118mg (0.45 mmol) triphenylphosphine, 82 mg (0.12 mmol) PdCl₂(PPh₃)₂ and6.3 mL (45.0 mmol) triethylamine in 7 mL dry THF. For the work-up thereaction mixture is diluted with ethyl acetate and small amounts ofcyclohexane, the organic phase is extracted with water and brine. Theproduct is purified by chromatography on silica gel using a hexane/ethylacetate gradient. Yield: 980 mg (99%).

A-14) 4-Trifluoromethyl-5-trimethylsilanylethynyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP2starting from 12.8 g (44 mmol)4-trifluoromethyl-5-iodo-pyridin-2-ylamine and 8.8 mL (62 mmol)1-trimethyl-silyl-ethyne using 844 mg (4.4 mmol) CuI, 3.1 g (4.4 mmol)PdCl₂(PPh₃)₂ and 62 mL (443 mmol) triethylamine in 80 mL dry THF. Forthe work-up the solvent is removed under reduced pressure, the crudeproduct is taken up in ethyl acetate and the organic phase is extractedwith water. The product is purified twice by chromatography on silicagel using a DCM/MeOH gradient. Yield: 5.85 g (51%).

A-15) 6-Trifluoromethyl-5-trimethylsilanylethynyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP2starting from 5.7 g (20 mmol) 6-trifluoromethyl-5-iodo-pyridin-2-ylamineand 3.9 mL (28 mmol) 1-trimethyl-silyl-ethyne using 379 mg (2.0 mmol)CuI, 1.4 g (2.0 mmol) PdCl₂(PPh₃)₂ and 28 mL (199 mmol) triethylamine in30 mL dry THF. For the work-up the solvent is removed under reducedpressure, the crude product is taken up in ethyl acetate and the organicphase is extracted with water. The product is purified by chromatographyon silica gel using a DCM/MeOH gradient. Yield: 2.83 g (55%).

A-16) 4-Methyl-5-trimethylsilanylethynyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP2starting from 3.3 g (14.1 mmol) 4-methyl-5-iodo-pyridin-2-ylamine and2.8 mL (19.7 mmol) 1-trimethyl-silyl-ethyne using 81 mg (1.4 mmol) CuI,296 mg (0.42 mmol) PdCl₂(PPh₃)₂, 370 mg (1.4 mmol) triphenylphosphineand 20 mL (141 mmol) triethylamine in 25 mL dry THF. After cooling toRT, the mixture is filtered and the product is isolated from thefiltrate by chromatography on silica gel using a DCM/MeOH gradient.Yield: 2.75 g (95%).

A-17) 6-Methyl-5-trimethylsilanylethynyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP2starting from 5.0 g (21.4 mmol) 6-methyl-5-iodo-pyridin-2-ylamine and4.5 mL (32 mmol) 1-trimethyl-silyl-ethyne using 407 mg (2.1 mmol) CuI,2.0 g (2.1 mmol) Pd(PPh₃)₄ and 30 mL (214 mmol) triethylamine in 40 mLdry DMF. For the work-up the solvent is removed under reduced pressureand the product is purified twice by chromatography on silica gel usinga DCM/MeOH gradient. Yield: 4.2 g (96%).

A-18) 4-Ethyl-5-trimethylsilanylethynyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP2starting from 10.3 g (41.6 mmol) 4-ethyl-5-iodo-pyridin-2-ylamine and8.2 mL (58.2 mmol) 1-trimethyl-silyl-ethyne using 792 mg (4.2 mmol) CuI,2.9 g (4.2 mmol) PdCl₂(PPh₃)₂ and 58 mL (416 mmol) triethylamine in 140mL dry THF. For the work-up the solvent is removed under reducedpressure, the crude product is taken up in ethyl acetate and the organicphase is extracted with water. The product is purified twice bychromatography on silica gel using a cyclohexane/ethyl acetate gradient.Yield: 9.08 g (100%).

A-19) 6-Ethyl-5-trimethylsilanylethynyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP2starting from 18 g (72.6 mmol) 6-ethyl-5-iodo-pyridin-2-ylamine and 14.4mL (102 mmol) 1-trimethyl-silyl-ethyne using 1.38 g (7.3 mmol) CuI, 5.1g (7.3 mmol) PdCl₂(PPh₃)₂ and 101 mL (726 mmol) triethylamine in 100 mLdry THF. For the work-up the solvent is removed under reduced pressure,the crude product is taken up in ethyl acetate and the organic phase isextracted with water. The product is purified twice by chromatography onsilica gel using a cyclohexane/ethyl acetate gradient. Yield: 12.73 g(80%).

A-20) 5-Trimethylsilanylethynyl-pyridin-3-ol

The title compound is synthesized according to general procedure GP2starting from 2.0 g (11.6 mmol) 5-bromo-3-hydroxy-pyridine and 2.3 mL(16.2 mmol) 1-trimethylsilyl-ethyne using 66 mg (0.3 mmol) CuI, 303 mg(1.2 mmol) triphenylphosphine, 243 mg (0.3 mmol) PdCl₂(PPh₃)₂ and 19 mL(139 mmol) triethylamine in 20 mL dry THF. For the work-up the reactionmixture is diluted with ethyl acetate and small amounts of cyclohexane,the organic phase is extracted with water and brine. The product ispurified by chromatography on silica gel using a DCM/MeOH gradient.Yield: 2.0 g (91%).

A-21) 5-Trimethylsilanylethynyl-pyridin-3-ylamine

The title compound is synthesized according to general procedure GP2starting from 2.0 g (11.6 mmol) 5-bromo-pyridin-3-ylamine and 2.3 mL(16.2 mmol) 1-trimethylsilyl-ethyne using 66 mg (0.3 mmol) CuI, 303 mg(1.2 mmol) triphenylphosphine, 243 mg (0.3 mmol) PdCl₂(PPh₃)₂ and 19 mL(139 mmol) triethylamine in 20 mL dry THF. For the work-up the reactionmixture is diluted with ethyl acetate and small amounts of cyclohexane,the organic phase is extracted with water and brine. The product ispurified by chromatography on silica gel using a DCM/MeOH gradient. Theproduct precipitated on the column and was subsequently extracted fromthe silica gel with pure MeOH. Yield: 2.0 g (91%).

A-22) 5-Trimethylsilanylethynyl-1H-pyrazolo[3,4-b]pyridine

The title compound is synthesized according to general procedure GP2starting from 1.0 g (5.1 mmol) 5-bromo-1H-pyrazolo[4,5-b]pyridine and1.0 mL (7.1 mmol) 1-trimethylsilyl-ethyne using 29 mg (0.15 mmol) CuI,133 mg (0.51 mmol) triphenylphosphine, 106 mg (0.15 mmol) PdCl₂(PPh₃)₂and 8.4 mL (60.6 mmol) triethylamine in 8 mL dry THF. The formedprecipitate is filtered off and the product is purified by RP-HPLC usingan ACN/H₂O gradient. Yield: 542 mg (50%).

A-23) 5-Trimethylsilanylethynyl-1H-pyrrolo[2,3-b]pyridine

The title compound is synthesized according to general procedure GP2starting from 3.0 g (15.2 mmol) 5-bromo-1H-pyrrolo[2,3-B]pyridine and3.0 mL (21.3 mmol) 1-trimethyl-silyl-ethyne using 87 mg (0.46 mmol) CuI,400 mg (1.5 mmol) triphenylphosphine, 312 mg (0.46 mmol) PdCl₂(PPh₃)₂and 25.4 mL (182 mmol) triethylamine in 25 mL dry THF. The formedprecipitate is filtered off and the product is purified bychromatography on silica gel using a DCM/MeOH gradient. Yield: 3.05 g(94%).

A-24) 6-Trimethylsilanylethynyl-3H-imidazo[4,5-b]pyridine

The title compound is synthesized according to general procedure GP2starting from 1.2 g (6.1 mmol) 5-bromo-3H-imidazo[4,5-b]pyridine and 1.2mL (8.4 mmol) 1-trimethylsilyl-ethyne using 34 mg (0.18 mmol) CuI, 159mg (0.61 mmol) triphenylphosphine, 128 mg (0.18 mmol) PdCl₂(PPh₃)₂ and10.1 mL (72.7 mmol) triethylamine in 10 mL dry THF. The formedprecipitate is filtered off and the product is purified by RP-HPLC usingan ACN/H₂O gradient. Yield: 606 mg (46%).

A-25) 5-Ethynyl-2-methyl-pyridine

The title compound is synthesized according to general procedure GP3starting from 2.2 g (12 mmol)2-methyl-5-trimethylsilanylethynyl-pyridine and 0.80 g (5.8 mmol) K₂CO₃in 13 mL MeOH. The crude product is purified by chromatography on silicagel using a cyclohexane/ethyl acetate gradient. The product is extractedfrom the organic phase with 1 N HCl and isolated as the hydrochlorideafter lyophilization. Yield: 1.3 g (73%).

A-26) 5-Ethynyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP3starting from 5.5 g (29 mmol)5-trimethylsilanylethynyl-pyridin-2-ylamine and 2.0 g (14 mmol) K₂CO₃ in30 mL MeOH. The product is purified by chromatography on silica gelusing a hexane/ethyl acetate gradient. Yield: 2.9 g (85%).

A-27) (5-Ethynyl-pyridin-2-yl)-methyl-amine

The title compound is synthesized according to general procedure GP3starting from 1.5 g (7.3 mmol)methyl-(5-trimethylsilanylethynyl-pyridin-2-yl)-amine and 507 mg (3.7mmol) K₂CO₃ in 10 mL MeOH. Yield: 698 mg (56%) after chromatography onsilica gel.

A-28) (5-Ethynyl-pyridin-2-yl)-ethyl-amine

The title compound is synthesized according to general procedure GP3starting from 980 mg (4.5 mmol) TMS-alkyne and 310 mg (2.3 mmol) K₂CO₃in 6 mL MeOH. Yield: 388 mg (59%) after chromatography on silica gel.

A-29) 5-Ethynyl-4-trifluoromethyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP3starting from 5.9 g (22.6 mmol)4-trifluoromethyl-5-trimethylsilanylethynyl-pyridin-2-ylamine and 1.56 g(11.3 mmol) K₂CO₃ in 50 mL MeOH. The product is purified bychromatography on silica gel using a DCM/MeOH gradient. Yield: 2.97 g(71%).

A-30) 5-Ethynyl-6-trifluoromethyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP3starting from 2.82 g (11.0 mmol)6-trifluoromethyl-5-trimethylsilanylethynyl-pyridin-2-ylamine and 757 mg(5.5 mmol) K₂CO₃ in 25 mL MeOH. The product is purified bychromatography on silica gel using a cyclohexane/ethyl acetate gradient.Yield: 0.9 g (44%).

A-31) 5-Ethynyl-4-methyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP3starting from 1.8 g (8.8 mmol)4-methyl-5-trimethylsilanylethynyl-pyridin-2-ylamine and 609 mg (4.4mmol) K₂CO₃ in 315 mL MeOH. The product is purified by chromatography onsilica gel using a DCM/MeOH gradient. Yield: 1.0 g (86%).

A-32) 5-Ethynyl-6-methyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP3starting from 4.3 g (21.0 mmol)6-methyl-5-trimethylsilanylethynyl-pyridin-2-ylamine and 1.5 g (10.5mmol) K₂CO₃ in 30 mL MeOH. The product is purified by chromatography onsilica gel using a DCM/MeOH gradient. Yield: 3.6 g.

A-33) 4-Ethyl-5-ethynyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP3starting from 3.3 g (15 mmol)4-ethyl-5-trimethylsilanylethynyl-pyridin-2-ylamine and 1.04 g (7.5mmol) K₂CO₃ in 30 mL MeOH. The product is purified by chromatography onsilica gel using a DCM/MeOH gradient. Yield: 1.78 g (81%).

A-34) 6-Ethyl-5-ethynyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP3starting from 12.23 g (56 mmol)6-ethyl-5-trimethylsilanylethynyl-pyridin-2-ylamine and 3.87 g (28 mmol)K₂CO₃ in 120 mL MeOH. The product is purified by chromatography onsilica gel using a DCM/MeOH gradient. Yield: 4.5 g (85%).

A-35) 5-Ethynyl-pyridin-3-ol

The title compound is synthesized according to general procedure GP3starting from 2.0 g (10.5 mmol) TMS-alkyne and 722 mg (5.2 mmol) K₂CO₃in 10 mL MeOH. Yield: 804 mg (49%) after chromatography on silica gel.

A-36) 5-Ethynyl-pyridin-3-ylamine

The title compound is synthesized according to general procedure GP3starting from 2.0 g (11 mmol) TMS-alkyne and 722 mg (5.2 mmol) K₂CO₃ in10 mL MeOH. Yield: 1.2 g (74%) after chromatography on silica gel andprecipitation from dioxane/HCl.

A-37) 5-Ethynyl-1H-pyrazolo[3,4-b]pyridine

The title compound is synthesized according to general procedure GP3starting from 542 mg (2.5 mmol) TMS-alkyne and 174 mg (1.3 mmol) K₂CO₃in 6 mL MeOH. Yield: 330 mg (92%) after extraction.

A-38) 5-Ethynyl-1H-pyrrolo[2,3-b]pyridine

The title compound is synthesized according to general procedure GP3starting from 3.1 g (14 mmol) TMS-alkyne and 983 mg (7.1 mmol) K₂CO₃ in15 mL MeOH. Yield: 1.2 g (61%) after chromatography on silica gel.

A-39) 6-Ethynyl-3H-imidazo[4,5-b]pyridine

The title compound is synthesized according to general procedure GP3starting from 706 mg (3.3 mmol) TMS-alkyne and 227 mg (1.6 mmol) K₂CO₃in 6 mL MeOH. Yield: 491 mg (94%) after extraction.

A-40) 4-Chloro-6-methyl-5-pyridin-3-ylethynyl-pyrimidine

The title compound is synthesized according to general procedure GP2starting from 250 mg (1.0 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin using123 mg (1.2 mmol) 3-ethynyl-pyridine, 18 mg (0.10 mmol) CuI, 34 mg (0.05mmol) bis-(triphenylphoshine)palladium(II) chloride, 0.5 mLtriethylamine in 2 mL DMF. The reaction mixture is stirred for 3 h at60° C. After removal of the solvent under reduced pressure, the productis purified by PR-HPLC. Yield: 25 mg (11%).

A-41) 5-(6-Amino-pyridin-3-ylethynyl)-4-chloro-6-methyl-pyrimidine

The title compound can be synthesized according to general procedure GP2starting from 30 g (0.11 mol) 4-chloro-5-iodo-6-methyl-pyrimidin (A-1)and 26.4 g (0.22 mol) of 5-ethynyl-pyridin-2-ylamie (A-36) using 2.1 g(11 mmol) copper iodide and 7.9 g (11 mmol)bis(triphenylphosphine)palladium chloride and triethylamine in 600 mLTHF. After work up and chromatography (silica, eluent 5% MeOH in DCM) 13g (45%) of the desired product is obtained.

A-42) 4-Chloro-6-ethyl-5-(6-methyl-pyridin-3-ylethynyl)-pyrimidine

The title compound is synthesized according to general procedure GP2starting from 250 mg (1.0 mmol) 4-chloro-6-ethyl-5-iodo-pyrimidine using121.5 mg (1.2 mmol) 5-ethynyl-2-methyl-pyridine, 18 mg (0.10 mmol) CuI,34 mg (0.05 mmol) bis-(triphenylphoshine)palladium(II) chloride, 0.5 mLtriethylamine in 2 mL DMF. The reaction mixture is stirred for 3 h at60° C. After removal of the solvent under reduced pressure, the productis purified by PR-HPLC. Yield: 25 mg (11%).

A-43) 5-(6-Amino-pyridin-3-ylethynyl)-4-chloro-6-ethyl-pyrimidine

To a stirred solution of 60 g (0.22 mol)4-chloro-5-iodo-6-ethyl-pyrimidin (A-2) in 1200 mL THF under argon isadded 4.2 g (22 mmol) CuI and 15.7 g (22 mmol)bis(triphenylphosphine)palladium chloride. The reaction mixture ispurged with argon for 30 min. 15.7 g (0.22 mol) of5-ethynyl-pyridin-2-ylamie (A-36) and triethylamine is added and thereaction mixture is heated at 60° C. for 4 h. After work up andchromatography (silica, eluent 5% MeOH in DCM) 26 g (45%) of the desiredproduct is obtained.

A-44)5-(6-Amino-2-methyl-pyridin-3-ylethynyl)-4-chloro-6-ethyl-pyrimidine

The title compound is synthesized according to general procedure GP2starting from 6.0 g (22.3 mmol) 4-chloro-6-ethyl-5-iodo-pyrimidine using3.5 g (26.8 mmol) 5-ethynyl-6-methyl-pyridin-2-ylamine, 213 mg (1.1mmol) CuI, 1.57 g (2.2 mmol) bis-(triphenyl-phoshine)palladium(II)chloride, 15 mL (112 mmol) triethylamine in 100 mL DME. The reactionmixture is stirred over night at RT. After removal of the solvent underreduced pressure, the residue is taken up in water and ethylacetate andthe aqueous phase is extracted twice with ethylacetate. The combinedorganic phases are dried over MgSO₄, filtered over silica and thesolvent is removed under reduced pressure. Yield: 2.9 g (64%)

A-45)[5-(4-Chloro-6-ethyl-pyrimidin-5-ylethynyl)-pyridin-2-yl]-methyl-amine

The title compound is synthesized according to general procedure GP2starting from 0.89 g (2.6 mmol) 4-chloro-6-ethyl-5-iodo-pyrimidine using0.48 g (3.65 mmol) (5-Ethynyl-pyridin-2-yl)-methyl-amine, 40 mg (0.21mmol) CuI, 180 mg (0.26 mmol) bis-(triphenyl-phoshine)palladium(II)chloride, 3.6 mL (26.1 mmol) triethylamine in 5.5 mL THF. The reactionmixture is stirred over night at 65° C. After removal of the solventunder reduced pressure, the residue is taken up in water andethylacetate and the aqueous phase is extracted twice with ethylacetate.The combined organic phases are dried over MgSO₄, filtered over silicaand the solvent is removed under reduced pressure. Yield: 320 mg (46%).

A-46)[5-(4-Chloro-6-ethyl-pyrimidin-5-ylethynyl)-pyridin-2-yl]-ethyl-amine

The title compound is synthesized according to general procedure GP2starting from 4-chloro-6-ethyl-5-iodo-pyrimidine using5-Ethynyl-pyridin-2-yl)-ethyl-amine (A-28), CuI,bis-(triphenyl-phoshine)palladium(II) chloride, triethylamine in THF.After work-up the desired compound is obtained in good yield andacceptable purity.

H2) 4-Bromo-2,6-difluorobenzoic acid

A solution of diisoporpylamine (32 g, 0.31 mol) in THF (170 ml) is addedn-BuLi (116 ml, 0.30 mol) drop wise, while keeping inner temperaturebelow −65° C. The mixture is stirred at −50° C. for 1 h to get LDAsolution. To a solution of compound H1 (50 g, 0.26 mol) in THF (170 mL)is added LDA, while keeping inner temperature below −65° C., thenstirred for 1.5 h and CO₂ is added at −65° C., followed adjusting pH to2˜3 with 1 N HCl, and extracted with EtOAc (3×500 ml). The organic layeris dried by Na₂SO₄, concentrated in vacuo to get compound H2 (39.0 g,63.4%).

H3) 4-Bromo-2,6-difluorobenzoic acid methyl ester

To a suspension of compound H2 (52.5 g, 0.23 mol) in MeOH (320 mL) isadded H₂SO₄ (98%) slowly. The reaction mixture is refluxed until TLCshows the starting material is consumed completely. The solvent isremoved and the resulting reside is partioned between saturated NaHCO₃and EtOAc. The organic layer is dried over anhydrous Na₂SO₄ andconcentrated under vacuum to give product H3 (50.0 g, 90.0%).

A-47)2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoicacidmethyl ester

A suspension of compound H3 (50.0 g, 0.20 mol), Bis(pinacolato)diborn(53.3 g, 0.21 mol), Pd(dppf)Cl₂ (15.0 g, 0.02 mol) and KOAc (61.5 g, 0.6mol) in dixoane (400 mL) is heated to 70° C. quickly for 2 h. Thedixoane is evaporated in vacuo and the resulting reside is washed withPE. The collected organic solution is concentrated in vacuo. The crudeproduct is crystallized from PE to give A-47 (52.76 g, 89.0%).

H5) 4-Bromo-2-chloro-6-fluorobenzoic acid

To a solution of diisopropylamine (2.4 g, 24 mmol) in THF (40 mL) isadded n-BuLi (8.8 mL, 22 mmol) dropwise at −78° C. The mixture isstirred at −78° C. for 1 h, and then allowed to warm to 0° C. Theresulting solution is transferred to a solution of compound H4 (4.16 g,20 mmol) in THF (60 mL) at −78° C. and stirred for 1 h, followedbubbling with dry CO₂ for another 1 h. The obtained solution is quenchedwith 1 N HCl (50 mL) at 0° C. and extracted with EtOAc (2×50 mL). Theorganic layers are washed with saturated aq. NaHCO₃ and brine, dried andconcentrated to afford a crude product H5 (isomer, 5 g, crude) as abrown oil, used for the next step directly.

H6) 4-Bromo-2-chloro-6-fluorobenzoic acid methyl ester

To a mixture of compound H5 (20 g, 80 mmol) and K₂CO₃ (13.2 g, 96 mmol)in DMF (200 mL) is added methyl iodide (23 g, 160 mmol). The mixture isstirred at ambient temperature for 2 h, poured into water (600 mL) andextracted with DCM (2×200 mL). The combined organic layers are washedwith water, brine, dried, and concentrated under reduced pressure toprovide a brown oil, purified by chromatography on silica gel(PE:EtOAc=100:1) to give compound H6 (isomer, 8 g, 49% for 2 steps) as alight yellow oil.

A-48) 2-Chloro6-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoicacidmethyl ester

A mixture of compound H6 (18 g, 68 mmol), bis(pinacolato)diboron (17.3g, 68 mmol), Pd(dppf)Cl₂ (2.5 g, 3.4 mmol) and KOAc (20 g, 0.2 mol) indioxane (300 mL) is heated to 80° C. for 2 h, and concentrated todryness under reduced pressure. The resulting residue is purified bychromatography on silica gel (PE: EtOAc=150:1) to give crude product asa clear oil, followed recrystallization with hexane to give A-48 (5.5 g,35.7%) as a white solid.

H8) 2,6-Dichloro-benzoic acid methyl ester

To a solution containing compound H7 (50 g, 0.26 mmol) and K₂CO₃ (53.8g, 0.39 mmol) in DMF (200 mL) was added methyl iodide (75.9 g, 0.52mmol). The mixture was stirred at ambient temperature for 2 h, pouredinto water (500 mL) and extracted with ethylacetate (2×500 mL). Thecombined ether layers were washed with water, brine, dried, filtered,and concentrated under reduced pressure to provide compound H8 (45 g,83%) as a yellow oil, Rf=0.8 (petrolether:ethylacetate=10:1).

A-49A)2,6-Dichloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoicacidmethyl ester

Bis(pinacolato)diboron [Pin₂B₂](44.8 g, 176 mmol),4,4′-Di-tert-butyl-[2,2′]bipyridinyl (120 mg, 0.44 mmol), and[Ir(COD)(OMe)]₂ (147 mg, 0.22 mmol) were added to a solution of compoundH8 (45 g, 0.22 mol) in heptane (500 mL). The reaction mixture turnedfrom yellow to forest green to brick red within the first minute. Thereaction mixture was heated to reflux for 18 h and then partitionedbetween ethyl acetate and water. The organic extracts were combined,dried over Na₂SO₄ and concentrated under reduced pressure. The solidresidue was purified by chromatography on silica gel (PE: EtOAc=50:1,detected by boric indicator) to afford the title compound (A-49A) as awhite solid (41.0 g, 53%). Rf=0.4 (petrolether: ethylacetate=20:1).

H10) 4-Bromo-2-trifluoromethyl-benzoic acid methyl ester

A solution of compound H9 (25.0 g, 94 mmol) in HCl-MeOH (250 mL) wasrefluxed overnight. TLC showed the starting material was consumedcompletely. The MeOH was evaporated in vacuo. And the resulting residewas partitioned between saturated NaHCO₃ and EtOAc. The organic layerwas dried over anhydrous Na₂SO₄ and concentrated under vacuum to giveproduct H10 (23.5 g; 90.0%).

A-49B)2-Trifluoromethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoicacidmethyl ester

A suspension of compound H10 (23.5 g, 83.3 mmol), Bis(pinacolato)diboron(21 g, 83.3 mmol), Pd(dppf)Cl₂ (6 g, 8.3 mmol) and KOAc (24 g, 25 mmol)in DMF (400 mL) was heated to 80° C. quickly for 2 h. The solvent wasevaporated in vacuo. The resulting residue was dissolved in PE, filteredand the filtrate was collected. The resulting filtrate was concentratedin vacuo to give crude product, crystallized in petrolether to giveA-49B (10.8 g; 40%).

H12) 4-Bromo-2-trifluoromethoxy-benzoic acid methyl ester

To a suspension of compound H11 (30.0 g, 0.11 mol) in 4 M MeOH—HCl (500mL) was refluxed overnight. The MeOH was evaporated in vacuo. And theresulting reside was partitioned between saturated Na₂CO₃ and EtOAc. Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated undervacuum to give product H12 (24.0 g; 77%).

A-49C)2-Trifluoromethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoicacidmethyl ester

A suspension of compound H12 (24 g, 0.08 mol), Bis(pinacolato)diboron(20.4 g, 0.08 mol) Pd(dppf)Cl₂ (1.0 g) and KOAc (15.68 g, 0.16 mol) indixoane (400 mL) was heated to 80° C. quickly for 2 h. The solvent wasevaporated in vacuo and the resulting residue was dissolved inpetrolether, filtered and the filtrate was collected. The resultingfiltrate was concentrated in vacuo to give crude product, crystallizedin petrolether to give A-49C (15.0 g; 63.2%).

A-50)4-[5-(6-Amino-2-methyl-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoicacid methyl ester

The title compound is synthesized in analogy to general procedure GP4starting from 3.9 g (14.3 mmol)5-(6-Amino-2-methyl-pyridin-3-ylethynyl)-4-chloro-6-ethyl-pyrimidineusing 3.7 g (18.6 mmol) 3-fluoro-4-methoxycarbonylphenyl boronic acid,502 g (0.71 mmol) bis-(triphenylphoshine)palladium(II) chloride, 10.7 mL(21.5 mmol) of an aqueous 2 M Cs₂CO₃ and 10 mL EtOH in 100 mL DME. Thereaction mixture is stirred over night at 80° C. The reaction mixture isfiltered over celite and the solvent is removed under reduced pressure.The crude product is triturated with water and ethylacetate. The phasesare separated and the aqueous is extracted twice with ethylacetate. Thecombined organic layers are dried over Mg2SO4 and the solvent isevaporated under reduced pressure. The crude is stirred with cyclohexaneand filtered off. After drying 4.0 g (72%) of the desired product isobtained as solid material, which is used without further purificationin the next step.

A-51)4-[5-(6-Amino-2-methyl-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoicacid

The title compound is synthesized according to general procedure GP8starting from 4.0 g (10.3 mmol)4-[5-(6-Amino-2-methyl-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoicacid methyl ester using 1.29 g (30.7 mmoL) LiOH in 40 mL water and 200mL THF. The reaction mixture is stirred over night at 50° C. The solventis removed under reduced pressure and the residue is taken up in water.Aqueous 1 M HCl is added until pH 5 is reached. The precipitated productis filtered off and washed with ACN. After drying 1.3 g (32%) of thedesired product are obtained a solid material.

A-52)5-[5-(6-Amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-pyridine-2-carboxylicacid

The title compound is synthesized in analogy to general procedure GP4starting from 1.2 g (4.63 mmol)4-chloro-6-ethyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine using 1.0 g(5.6 mmol) 4-methoxycarbonyl-3-pyridyl boronic acid, 163 mg (0.23 mmol)bis-(triphenylphoshine)palladium(II) chloride, 7.0 mL (13.9 mmol) of anaqueous 2 M Cs₂CO₃ and 2 mL MeOH in 10 mL DME. The reaction mixture isstirred over night at 80° C. The reaction mixture is poured on water andwashed with DCM. Aqueous 1 M HCl is added to the aqueous phase until pH5 is reached. The precipitated product is filtered off and washed withwater and methanol. After drying 290 mg (13%) of the desired product areobtained a solid material which is used for the next step withoutfurther purification.

A-72)4-[5-(6-Amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoicacid methyl ester

The title compound is synthesized in analogy to general procedure GP4starting from 15 g (58.06 mmol)4-chloro-6-ethyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine using 13.8 g(69.6 mmol) 3-fluoro-4-methoxycarbonylphenyl boronic acid, 1.51 g (2.15mmol) bis-(triphenylphoshine)palladium(II) chloride, 43.5 mL (87.0 mmol)of an aqueous 2 M Cs₂CO₃ and 20 mL EtOH in 200 mL DME. The reactionmixture is stirred over night at 80° C. The reaction mixture is filteredover celite and the solvent is removed under reduced pressure. The crudeproduct is triturated with water and sonicated for 30 min. Theprecipitated product is filtered off, washed with ACN and a small amountof MeOH. After drying 14.8 g (68%) of the desired product is obtained assolid material.

A-73)4-[5-(6-Amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoicacid

The title compound is synthesized according to general procedure GP8starting from 17.8 g (47.3 mmol)4-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoicacid methyl ester using 3.97 g (94.6 mmoL) LiOH in 30 mL water and 300mL THF. The reaction mixture is stirred over night at RT. The solvent isremoved under reduced pressure and the residue is taken up in water.Aqueous 1 M HCl is added until pH 5 is reached. The precipitated productis filtered off and washed with ACN. After drying 17.1 g (85%) of thedesired product are obtained a solid material.

A-74) 4-[5-(6-Amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-benzoicacid methyl ester

The title compound is synthesized according to general procedure GP4starting from 2.0 g (7.73 mmol)4-chloro-6-ethyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine using 2.1 g(11.6 mmol) 4-methoxycarbonylphenyl boronic acid, 271.3 mg (0.39 mmol)bis-(triphenylphoshine)palladium(II) chloride, 5.7 mL (11.5 mmol) of anaqueous 2 M Cs₂CO₃ solution and 2 mL EtOH in 5 mL DME. The reactionmixture is stirred for 1 h at 130° C. in the microwave. The reactionmixture is suspended in MeOH and the precipitated product is filteredoff and washed with MeOH. After drying 2.25 g (81%) of the desiredproduct are obtained as solid material.

A-75) 4-[5-(6-Amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-benzoicacid

The title compound is synthesized according to general procedure GP8starting from 2.25 g (6.28 mmol)4-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-benzoic acidmethyl ester using 1.32 g (31.4 mmoL) LiOH in 5 mL water and 50 mL THF.The reaction mixture is stirred over night at 50° C. The solvent isremoved under reduced pressure and the residue is taken up in water.Aqueous 1 M HCl is added until pH 5 is reached. The precipitated productis filtered off and taken up in water. After freeze drying 2.3 g ofcrude product are obtained which is used for the next step withoutfurther purification.

A-76)4-[5-(6-Amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-chloro-benzoicacid methyl ester

The title compound is synthesized according to general procedure GP4starting from 4.0 g (15.5 mmol)4-chloro-6-ethyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine using 4.3 g(20.1 mmol) 3-chloro-4-methoxycarbonylphenyl boronic acid, 543 mg (0.77mmol) bis-(triphenylphoshine)palladium(II) chloride, 11.6 mL (23.2 mmol)of an aqueous 2 M Cs₂CO₃ and 10 mL EtOH in 100 mL DME. The reactionmixture is stirred over night at 80° C. The solvent is removed underreduced pressure and the residue is taken up in water and ethylacetate.The aqueous phase is extracted twice with ethylacetate. The combinedorganic layers are dried over MgSO₄ filtered over celite and the solventis removed under reduced pressure. After drying 3.3 g (54%) of thedesired product is obtained.

A-77)4-[5-(6-Amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-chloro-benzoicacid

The title compound is synthesized according to general procedure GP8starting from 3.3 g (8.4 mmol)4-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-chloro-benzoicacid methyl ester using 1.06 g (25.2 mmoL) LiOH in 20 mL water and 100mL THF. The reaction mixture is stirred over night at 50° C. The solventis removed under reduced pressure and the residue is taken up in water.Aqueous 1 M HCl is added until pH 5-6 is reached. The precipitatedproduct is filtered off and washed with water and MeOH. After drying 2.5g (89%) of the desired product are obtained as solid material.

A-78)4-[5-(6-Amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-benzoic acidmethyl ester

The title compound is synthesized according to general procedure GP4starting from 2.0 g (8.2 mmol)4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine using 2.2 g(12.3 mmol) 4-methoxycarbonylphenyl boronic acid, 240 mg (1.5 mmol) 287mg (0.41 mmol) bis-(triphenylphoshine)palladium(II) chloride, 6.1 mL(12.3 mmol) of an aqueous 2 M Cs₂CO₃ and 2 mL EtOH in 5 mL DME. Thereaction mixture is stirred for 1 h at 130° C. in the microwave. Thereaction mixture is suspended in MeOH and the precipitated product isfiltered off and washed with MeOH. After drying 2.2 g (77%) of thedesired product are obtained as solid material.

A-79)4-[5-(6-Amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-benzoic acid

The title compound is synthesized according to general procedure GP8starting from 2.2 g (6.3 mmol)4-[5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-benzoic acidmethyl ester using 1.33 g (31.6 mmoL) LiOH in 5 mL water and 50 mL THF.The reaction mixture is stirred over night at 50° C. The solvent isremoved under reduced pressure and the residue is taken up in water.Aqueous 1 M HCl is added until pH 5 is reached. The precipitated productis filtered off and taken up in water. After freeze drying 2.7 g ofcrude product are obtained which is used for the next step withoutfurther purification.

A-80)4-[5-(6-Amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-2-chlorobenzoic acid methyl ester

The title compound is synthesized according to general procedure GP4starting from 10 g (40.9 mmol)4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine using 10.5g (49.0 mmol) 2-chloro-4-methoxycarbonylphenyl boronic acid, 1.43 g(2.04 mmol) bis-(triphenylphosphine)palladium(II) chloride, 61.3 mL (122mmol) of an aqueous 2 M Cs₂CO₃ solution and 50 mL EtOH in 500 mL DME.The reaction mixture is stirred for 3 h at 80° C. The reaction mixtureis filtered over celite and the solvent is removed under reducedpressure. Water is added and the precipitated product is filtered offand washed with ACN and MeOH. After drying 13.8 g of crude product areobtained which is used in the next step without further purification.

A-81)4-[5-(6-Amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-2-chlorobenzoic acid

The title compound is synthesized according to general procedure GP8starting from 13.8 g (36.4 mmol)4-[5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-2-chloro-benzoicacid methyl ester using 7.64 g (182 mmoL) LiOH in 200 mL water and 400mL THF. The reaction mixture is stirred over night at 50° C. The solventis removed under reduced pressure and the residue is taken up in water.Aqueous 1 M HCl is added until pH 5-6 is reached. The precipitatedproduct is filtered off and washed with water and MeOH. After drying12.1 g of the desired product is obtained, which is used for the nextstep without further purification.

A-82)4-[5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-2-fluorobenzoic acid methyl ester (C-45)

The title compound is synthesized according to general procedure GP4starting from 2.0 g (8.2 mmol)4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine using 2.9 g(14.7 mmol) 2-fluoro-4-methoxycarbonylphenyl boronic acid, 287 mg (0.41mmol) bis-(triphenylphoshine)palladium(II) chloride, 6.1 mL (12.3 mmol)of an aqueous 2 M Cs₂CO₃ solution and 2 mL EtOH in 5 mL DME. Thereaction mixture is stirred for 1 h at 130° C. in the microwave. Thereaction mixture is suspended in MeOH and the precipitated product isfiltered off and washed with MeOH. After drying, 2.3 g (77%) of thedesired product is obtained as solid material.

A-83)4-[5-(6-Amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-2-fluorobenzoic acid

The title compound is synthesized according to general procedure GP8starting from 2.28 g (6.29 mmol)4-[5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-2-fluorobenzoic acid methyl ester using 1.32 g (31.5 mmoL) LiOH in 5 mL waterand 50 mL THF. The reaction mixture is stirred over night at 50° C. Thesolvent is removed under reduced pressure and the residue is taken up inwater. Aqueous 1 M HCl is added until pH 5 is reached. The precipitatedproduct is filtered off and taken up in water. After freeze drying 2.7 gof crude product is obtained which is used for the next step withoutfurther purification.

A-84)5-[5-(6-Amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoicacid methyl ester

The title compound is synthesized according to general procedure GP4starting from 1.5 g (5.8 mmol)4-chloro-6-ethyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine using 1.7 g(8.7 mmol) (4-fluoro-3-methoxycarbonyl)phenyl boronic acid, 203 mg (0.29mmol) bis-(triphenylphoshine)palladium(II) chloride, 1.94 g (13.9 mmol)K₂CO₃ in 18 mL DME/H₂O/EtOH (10:5:1 v/v/v). The reaction mixture isstirred for 3 h at 80° C. The mixture is filtered over celite and thesolvent is removed under reduced pressure. Water is added and theprecipitated product is filtered off and washed with ACN and MeOH. Afterdrying 1.5 g (68%) of crude product is obtained which is used for thenext step without further purification.

A-85)5-[5-(6-Amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoicacid

The title compound is synthesized according to general procedure GP8starting from 1.5 g (3.98 mmol)5-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoicacid methyl ester using 334 mg (7.97 mmol) LiOH in 20 mL THF and 5 mLwater. The reaction mixture is stirred over night at 50° C. Aqueous 1 MHCl is added until pH 5 is reached. The solvent is removed under reducedpressure and the residue is stirred in MeOH. After drying the crudeproduct (0.8 g) is used in the next step without further purification.

A-86)4-[5-(6-Amino-2-methyl-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoicacid methyl ester

The title compound is synthesized according to general procedure GP4starting from 3.90 g (14.3 mmol)4-chloro-6-ethyl-5-(6-amino-2-methyl-pyridin-3-ylethynyl)-pyrimidineusing 3.38 g (18.6 mmol) 3-fluoro-4-methoxycarbonylphenyl boronic acid,502 mg (0.71 mmol) bis-(triphenylphoshine)palladium(II) chloride, 10.7mL (21.5 mmol) of an aqueous 2 M Cs₂CO₃ solution and 10 mL EtOH in 100mL DME. The reaction mixture is stirred over night at 80° C. The solventis removed under reduced pressure and the residue is taken up in waterand ethylacetate. The aqueous phase is extracted twice withethylacetate. The combined organic layers are dried over MgSO₄ filteredover celite and the solvent is removed under reduced pressure. Afterdrying 4.0 g (72%) of the desired product is obtained.

A-87)4-[5-(6-Amino-2-methyl-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoicacid

The title compound is synthesized according to general procedure GP8starting from 4.0 g (10.2 mmol)4-[5-(6-amino-2-methyl-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoicacid methyl ester using 1.29 g (30.7 mmoL) LiOH in 40 mL water and 200mL THF. The reaction mixture is stirred over night at 50° C. The THF isremoved under reduced pressure and the residue is taken up in water.Aqueous 1 M HCl is added until pH 5-6 is reached. The precipitatedproduct is filtered off and washed with water and MeOH. After drying1.25 g (32%) of the desired product is obtained a solid material.

A-92)4-[5-(6-Amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-methoxy-benzoicacid methyl ester

The title compound is synthesized according to general procedure GP4starting from 2.5 g (9.7 mmol)4-chloro-6-ethyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine using 2.4 g(11.6 mmol) 3-methoxy-4-methoxycarbonylphenyl boronic acid, 339 mg (0.48mmol) bis-(triphenylphoshine)palladium(II) chloride, 14 mL (28.2 mmol)of an aqueous 2 M Cs₂CO₃ and 5 mL MeOH in 50 mL DME. The reactionmixture is stirred for 2 hours at 90° C. The solvent is removed underreduced pressure and the residue is taken up in water and ethylacetate.The aqueous phase is extracted twice with ethylacetate. The combinedorganic layers are dried over MgSO₄ filtered over celite and the solventis removed under reduced pressure. After drying 3.3 g (89%) of thedesired product is obtained.

A-93)4-[5-(6-Amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-methoxy-benzoicacid

The title compound is synthesized according to general procedure GP8starting from 7.5 g (19.3 mmol)4-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-methoxy-benzoicacid methyl ester using 4.05 g (96.5 mmoL) LiOH in 100 mL water and 200mL THF. The reaction mixture is stirred over night at room temperature.The solvent is removed under reduced pressure and the residue is takenup in water. Aqueous 1 M HCl is added until pH 5-6 is reached. Theprecipitated product is filtered off and washed with water andAcetonitrile. After drying 6.5 g (89%) of the desired product isobtained as solid material.

Intermediates A-94 to A-96G can be synthesized according to the generalprocedure GP4 (Suzuki reaction) outlined above. The appropriate halidesrequired for synthesis can be deduced from the table of examples.

TABLE 1A Examples A-94-A-96G MW Nr. Structure Int. 1 Int. 2 MW [M + H]A-94

A-43 A-47 394.38 395 A-95

A-43 A-48 410.84 412 A-96

A-43 3,5-dichloro-4- methoxycarbonyl- phenyl boronic acid 427.29 428A-96A

A-45 A-49A 390.42 392 A-96B

A-45 A-47 408.40 410 A-96C

A-45 A-49A 441.32 443 A-96D

A-43 3-methyl-4- methoxycarbonyl- phenyl boronic acid 372.43 374 A-96E

A-43 A-49B 426.40 428 A-96F

A-43 A-49C 442.40 A-96G

A-46 3-fluoro-4- methoxycarbonyl- phenyl boronic acid 404.45 406

Intermediates A-100 to A-109 can be synthesized according to the generalprocedure GP8 outlined above. The appropriate methylesters required forsynthesis can be deduced from the table of examples.

TABLE 1B Examples A-100-A-109 Inter- MW Nr. Structure mediate 1 MW [M +H] A-100

A-94 380.36 382 A-101

A-95 396.81 398 A-102

A-96 413.27 415 A-103

A-96A 376.39 378 A-104

A-96B 394.38 396 A-105

A-96C 427.29 429 A-106

A-96D 358.40 360 A-107

A-96E 412.37 414 A-108

A-96F 428.37 430 A-109

A-96G 390.42 392

Examples C

Examples C-1 to C-50 can be synthesized according to the generalprocedures GP4 (Suzuki reaction) outlined above. The appropriate halidesrequired for synthesis can be deduced from the table of examples.

TABLE 2 Examples C-1-C-53 MW EC₅₀ PC3 Nr. Structure Int. MW [M + H]t_(R) [min] [nM] C-1

A-43 367.45 368 1.78 49 C-2

A-41 353.43 354 1.65 85 C-3

A-43 329.41 330 1.57 78 C-4

A-43 329.41 330 1.54 60 C-5

A-41 377.83 378 1.32 50 C-6

A-41 357.42 358 1.34 77 C-7

A-41 286.34 287 1.47 163 C-8

A-41 364.43 365 1.3 173 C-9

A-41 375.41 376 1.39 275 C-10

A-41 357.42 358 1.35 134 C-11

A-41 375.41 376 1.38 67 C-12

A-43 391.86 392 1.45 46 C-13

A-43 300.36 301 1.63 170 C-14

A-43 378.45 379 1.47 100 C-15

A-43 389.43 390 1.53 142 C-15A

A-43 389.43 390 1.55 74 C-16

A-42 390.87 391/ 393 1.64 627 C-17

A-42 377.47 378 1.63 603 C-18

A-42 370.45 371 1.64 612 C-19

A-42 388.44 289 1.71 506 C-20

A-41 301.35 302 1.33 191 C-21

A-41 355.32 356 (564) 1.60 (1.70) 265 C-22

A-41 337.38 338 1.50 163 C-23

A-41 317.35 318 1.45 245 C-24

A-41 301.35 302 1.34 153 C-25

A-41 370.46 371 1.62 407 C-26

A-41 327.39 328 1.53 170 C-27

A-43 315.38 316 1.47 138 C-28

A-43 369.35 370 1.74 139 C-29

A-43 351.41 352 1.63 123 C-30

A-43 331.38 332 1.59 178 C-31

A-43 315.38 316 1.46 133 C-32

A-43 386.46 387 1.56 95 C-33

A-43 331.38 332 1.59 106 C-34

A-43 344.42 345 1.58 78 C-35

A-43 341.42 342 1.65 131 C-36

A-41 385.47 386 1.53 590 C-37

A-41 399.45 400 1.34 644 C-38

A-41 391.86 392 1.53 245 C-39

A-41 417.44 418 1.23 255 C-40

A-41 433.90 434 (623) 1.29 (1.38) 348 C-41

A-41 415.47 416 1.46 679 C-42

A-41 431.92 430 1.69 503 C-43

A-41 361.38 362 1.30 463 C-44

A-43 399.50 400 1.64 543 C-45

A-43 405.89 406 1.47 90 C-46

A-43 431.47 432 1.51 228 C-47

A-43 433.94 434 1.66 517 C-48

A-43 445.95 446 1.69 747 C-49

A-43 391.86 392 1.46 506 C-50

A-43 357.42 358 1.38 212

Examples D

Examples D-1 to D-240 can be synthesized according to the generalprocedures GP9 (amide formation) outlined above. The appropriateintermediates required for synthesis can be deduced from the table ofexamples.

TABLE 3 Examples D-1-D240 MW EC₅₀ PC3 Nr. Structure Int. MW [M + H]t_(R) [min] [nM] D-1

A-73 447.51 448 1.66 77 D-2

A-73 446.53 447 1.62 148 D-3

A-73 472.57 473 1.63 217 D-4

A-73 433.48 434 1.49 33 D-5

A-73 375.41 376 1.50 125 D-6

A-73 419.46 420 1.45 32 D-7

A-73 433.48 434 1.63 24 D-8

A-73 444.51 445 1.57 49 D-9

A-73 460.55 461 1.68 140 D-10

A-87 443.52 444 1.78 42 D-11

A-77 445.95 446 1.80 51 D-12

A-87 508.55 509 1.74 45 D-13

A-87 484.58 485 1.77 53 D-14

A-87 511.52 512 1.91 72 D-15

A-87 528.63 529 1.61 51 D-16

A-87 528.63 529 1.72 67 D-17

A-87 562.67 563 1.53 76 D-18

A-87 498.60 499 1.75 41 D-19

A-87 536.63 537 1.64 30 D-20

A-87 445.50 446 1.57 14 D-21

A-87 458.54 459 1.57 27 D-22

A-87 540.68 541 2.23 355 D-23

A-87 529.62 530 1.55 41 D-24

A-87 534.64 535 1.96 52 D-25

A-87 520.61 521 1.96 55 D-26

A-87 515.63 516 1.63 140 D-27

A-77 518.06 518 1.63 96 D-28

A-77 487.00 487/ 489 1.78 9 D-29

A-77 503.05 503 1.93 56 D-30

A-77 463.97 464/ 466 1.68 71 D-31

A-77 531.06 531/ 533 1.62 23 D-32

A-77 565.10 565 1.53 38 D-33

A-77 435.91 436/ 438 1.53 45 D-34

A-77 435.91 436 1.45 36 D-35

A-77 449.94 450/ 452 1.64 35 D-36

A-77 490.99 491/ 493 1.47 41 D-37

A-77 524.03 524 1.82 38 D-38

A-77 515.06 515 1.90 65 D-39

A-77 523.04 523 1.97 67 D-40

A-77 513.95 514 1.93 130 D-41

A-77 510.97 511 1.75 28 D-42

A-77 489.02 487 1.78 16 D-43

A-77 503.05 503 1.86 28 D-44

A-77 460.92 461 1.43 56 D-45

A-77 474.99 475 1.68 54 D-46

A-77 488.98 489 1.51 74 D-47

A-93 506.55 507 1.64 58 D-48

A-93 498.63 499 1.76 58 D-49

A-93 482.59 483 1.66 43 D-50

A-93 484.60 485 1.65 80 D-51

A-93 526.64 527 1.52 30 D-52

A-93 500.60 501 1.53 71 D-53

A-93 470.57 471 1.57 67 D-54

A-93 524.54 525 1.77 38 D-55

A-93 534.64 535 1.57 36 D-56

A-93 484.56 485 1.42 115 D-57

A-93 486.57 487 1.39 357 D-58

A-93 456.55 457 1.47 49 D-59

A-93 456.50 457 1.34 248 D-60

A-93 513.64 514 1.56 480 D-61

A-73 494.52 495 1.73 22 D-62

A-73 527.64 528 1.57 56 D-63

A-73 514.60 515 1.62 30 D-64

A-73 527.64 528 1.68 71 D-65

A-73 458.54 459 1.59 156 D-66

A-73 459.52 460 1.54 46 D-67

A-73 610.78 611 1.67 105 D-68

A-73 391.40 392 1.11 24 D-69

A-73 512.51 513 (775) 1.84 (1.89) 51 D-70

A-73 512.63 513 1.88 80 D-71

A-73 445.50 446 1.45 32 D-73

A-73 486.59 487 1.74 179 D-74

A-73 472.57 473 1.69 128 D-75

A-73 458.54 459 1.68 147 D-76

A-73 486.59 487 1.74 93 D-77

A-73 472.57 473 1.70 80 D-78

A-73 541.67 542 1.63 53 D-79

A-73 487.58 488 1.64 33 D-80

A-73 487.58 488 1.70 53 D-81

A-73 447.51 448 1.55 72 D-82

A-41 486.55 487 1.52 50 D-83

A-73 486.59 487 1.90 36 D-84

A-73 514.60 515 1.60 17 D-85

A-73 515.59 516 1.54 56 D-86

A-73 548.64 549 1.51 39 D-87

A-73 484.58 485 1.73 54 D-88

A-73 514.60 515 1.70 68 D-89

A-73 522.60 523 1.62 42 D-90

A-73 472.52 473 1.47 48 D-91

A-73 474.54 475 1.45 44 D-92

A-73 507.57 508 1.8 76 D-93

A-73 507.57 508 1.62 76 D-94

A-73 526.66 527 2.22 602 D-95

A-73 488.56 489 1.6 40 D-96

A-73 498.60 499 1.87 63 D-97

A-73 520.61 521 1.95 151 D-98

A-73 506.58 507 1.95 78 D-99

A-73 501.61 502 1.62 78 D-100

A-73 472.57 473 1.63 44 D-101

A-73 445.50 446 1.56 12 D-103

A-73 502.59 503 1.62 58 D-104

A-73 473.55 474 1.57 62 D-105

A-73 463.53 462 1.39 50 D-106

A-73 484.58 485 1.77 42 D-107

A-73 459.52 460 1.66 25 D-108

A-73 512.63 513 1.90 41 D-110

A-73 445.50 446 1.51 30 D-111

A-73 526.66 527 2.05 87 D-112

A-73 498.60 499 1.77 61 D-113

A-73 430.48 431 1.42 80 D-114

A-73 541.67 542 1.85 39 D-116

A-73 502.55 503 1.72 22 D-117

A-73 511.56 512 1.48 244 D-118

A-73 458.54 459 1.57 48 D-119

A-73 486.55 487 1.49 114 D-120

A-73 459.52 458 1.69 199 D-121

A-73 470.55 471 1.59 17 D-122

A-73 472.57 473 1.58 15 D-123

A-73 513.49 514 1.56 76 D-124

A-73 487.58 488 1.58 43 D-125

A-73 473.55 474 1.48 93 D-126

A-73 521.59 522 1.63 144 D-127

A-73 472.57 473 1.48 80 D-128

A-73 458.54 459 1.43 65 D-129

A-73 486.59 487 1.74 30 D-130

A-73 500.62 501 1.96 45 D-131

A-73 445.50 446 1.37 57 D-132

A-73 458.54 459 1.38 98 D-133

A-73 458.49 459 1.29 27 D-134

A-73 456.52 455 1.51 316 D-135

A-73 445.50 446 1.55 122 D-136

A-77 501.03 499/ 501 1.83 106 D-138

A-77 504.03 504 1.69 95 D-139

A-77 543.11 543/ 545 1.96 146 D-140

A-77 474.99 475/ 477 1.68 221 D-141

A-77 479.99 478 1.44 39 D-142

A-77 475.98 476/ 478 1.72 80 D-143

A-77 475.98 474/ 476 1.6 76 D-145

A-77 447.92 448/ 450 1.49 76 D-146

A-77 447.92 448 1.49 79 D-147

A-77 461.95 460/ 462 1.57 33 D-148

A-77 543.11 543 2.08 115 D-149

A-77 489.02 487/ 489 1.69 105 D-150

A-77 474.99 475/ 477 1.64 88 D-151

A-77 515.06 515/ 517 1.84 83 D-152

A-77 446.94 447 1.48 73 D-153

A-77 407.86 408 1.11 55 D-154

A-77 474.99 475/ 477 1.64 122 D-155

A-77 524.03 524 1.68 64 D-156

A-77 461.95 462/ 464 1.52 40 D-157

A-77 461.95 462/ 464 1.63 43 D-159

A-77 461.95 462 1.58 38 D-160

A-77 537.06 M + H = 7/539 2.10 133 D-161

A-93 498.63 499 1.66 156 D-162

A-93 499.61 500 1.41 124 D-163

A-93 539.68 540 1.33 293 D-164

A-93 457.53 458 1.29 91 D-165

A-93 526.64 527 1.35 167 D-166

A-93 443.50 444 1.32 116 D-167

A-93 445.48 446 1.21 383 D-168

A-93 429.48 430 1.31 105 D-169

A-93 484.60 485 1.41 Nd D-170

A-93 524.67 525 1.84 Nd D-172

A-93 560.68 561 1.47 392 D-173

A-93 470.57 471 1.53 Nd D-174

A-93 470.57 469 1.53 282 D-175

A-93 496.61 497 1.66 95 D-176

A-93 538.69 539 1.95 384 D-177

A-93 484.60 485 1.58 280 D-178

A-93 417.47 418 1.36 85 D-179

A-93 505.60 506 1.31 134 D-180

A-93 514.58 515 1.67 121 D-181

A-93 524.67 523 1.81 205 D-182

A-93 486.57 487 1.30 180 D-183

A-93 498.58 499 1.20 218 D-185

A-93 538.69 539 (762) 1.94 (2.03) 1140 D-186

A-93 510.64 511 1.62 190 D-187

A-93 532.64 533 1.71 296 D-188

A-79 474.57 475 1.74 62 D-189

A-79 456.55 457 1.43 63 D-190

A-79 454.58 455 1.72 62 D-191

A-79 452.56 453 1.54 55 D-192

A-79 516.62 517 1.34 140 D-193

A-79 482.59 483 1.42 69 D-194

A-79 442.52 443 1.29 134 D-195

A-79 466.59 467 1.68 51 D-196

A-73 462.53 463 1.52 144 D-197

A-73 458.54 459; tR = 1.68 1.68 122 D-198

A-73 513.62 514 1.52 55 D-199

A-73 444.51 445 1.57 127 D-200

A-73 472.57 473 1.81 451 D-201

A-73 502.59 503 1.60 90 D-202

A-73 514.65 515 1.90 200 D-203

A-73 431.47 432 1.43 58 D-204

A-73 431.47 432 1.42 53 D-205

A-73 541.67 542 1.80 308 D-206

A-73 514.60 515 1.50 154 D-207

A-73 498.60 499 1.80 71 D-208

A-73 567.71 568 1.88 118 D-209

A-73 484.58 485 1.75 77 D-210

A-73 527.64 528 1.68 172 D-211

A-73 472.52 473 1.47 141 D-212

A-73 479.53 480 1.49 75 D-213

A-73 500.62 501 1.76 132 D-214

A-73 445.50 446 1.55 45 D-215

A-73 458.54 459 1.57 64 D-216

A-73 493.56 494 1.52 42 D-217

A-73 474.54 475 1.55 97 D-218

A-73 417.44 418 1.56 57 D-219

A-73 431.47 432 1.68 58 D-220

A-73 433.44 433 1.41 65 D-221

A-73 405.43 406 1.60 35 D-222

A-75 399.45 400 1.52 63 D-223

A-75 413.48 414 1.62 85 D-224

A-75 415.45 416 1.39 106 D-225

A-75 387.44 388 1.54 66 D-226

A-83 403.42 404 1.44 49 D-227

A-83 417.44 418 (363) 1.55 (1.63) 100 D-228

A-83 419.41 420 1.30 82 D-229

A-83 391.40 392 1.47 64 D-230

A-81 419.87 420/ 422 1.47 62 D-231

A-81 433.90 434/ 436 1.59 78 D-232

A-81 435.87 436/ 438 1.34 101 D-233

A-81 407.86 408/ 410 1.52 61 D-234

A-73 500.58 501 1.36 73 D-235

A-73 484.58 485 1.52 78 D-236

A-73 458.54 459 1.40 49 D-237

A-73 458.54 459 1.40 77 D-238

A-73 486.59 487 1.58 71 D-239

A-73 431.47 432 1.38 53 D-240

A-52 427.51 428 1.41 248

Examples E

Examples E-1 to E-349 can be synthesized according to the generalprocedure GP9 (Amide formation) outlined above. The appropriateintermediates for synthesis can be deduced from the table of theexamples.

TABLE 4 Examples E-1-E-349 MW Nr. Structure Int. MW [M + H] tR [min] E-1

A-100 462.5 463 1.63 E-2

A-100 490.56 491 1.82 E-3

A-100 476.53 477 1.72 E-4

A-100 490.56 491 1.86 E-5

A-100 506.55 507 1.68 E-6

A-100 532.59 533 1.68 E-7

A-100 502.57 503 1.86 E-8

A-100 504.58 505 1.94 E-9

A-100 532.59 533 1.65 E-10

A-100 407.42 408 1.63 E-11

A-100 433.46 434 1.73 E-12

A-100 393.4 394 1.5 E-13

A-100 492.53 493 1.55 E-14

A-100 448.47 449 1.50 E-15

A-73 459.52 458 1.69 E-16

A-73 456.52 455 1.51 E-17

A-73 445.5 446 1.55 E-18

A-77 501.03 499/501 1.83 E-19

A-77 518.01 518/520 1.74 E-20

A-77 504.03 504 1.69 E-21

A-77 543.11 543/545 1.96 E-22

A-77 474.99 475/477 1.68 E-23

A-77 479.99 478 1.44 E-24

A-77 475.98 476/478 1.72 E-25

A-77 475.98 474/476 1.6 E-26

A-77 529.08 529/531 1.81 E-27

A-77 447.92 448/450 1.49 E-28

A-77 447.92 448 1.49 E-29

A-77 461.95 460/462 1.57 E-30

A-77 543.11 543 2.08 E-31

A-77 489.02 487/489 1.69 E-32

A-77 474.99 475/477 1.64 E-33

A-77 515.06 515/517 1.84 E-34

A-77 446.94 447 1.48 E-35

A-77 407.86 408 1.11 E-36

A-77 474.99 475/477 1.64 E-37

A-77 524.03 524 1.68 E-38

A-77 461.95 462/464 1.52 E-39

A-77 461.95 462/464 1.63 E-40

A-77 501.03 501 1.72 E-41

A-77 461.95 462 1.58 E-42

A-77 537.06 537/539 2.1 E-43

A-93 498.63 499 1.66 E-44

A-93 499.61 500 1.41 E-45

A-93 539.68 540 1.33 E-46

A-93 457.53 458 1.29 E-47

A-93 526.64 527 1.35 E-48

A-93 443.5 444 1.32 E-49

A-93 445.48 446 1.21 E-50

A-93 429.48 430 1.31 E-51

A-93 484.6 485 1.41 E-52

A-93 524.67 525 1.84 E-53

A-93 524.67 525 1.56 E-54

A-93 560.68 561 1.47 E-55

A-93 470.57 471 1.53 E-56

A-93 470.57 469 1.53 E-57

A-93 496.61 497 1.66 E-58

A-93 538.69 539 1.95 E-59

A-93 484.6 485 1.58 E-60

A-93 417.47 418 1.36 E-61

A-93 505.6 506 1.31 E-62

A-93 514.58 515 1.67 E-63

A-93 524.67 523 1.81 E-64

A-93 486.57 487 1.3 E-65

A-93 498.58 499 1.2 E-66

A-93 496.61 497 1.45 E-67

A-93 538.69 539 1.94 E-68

A-93 510.64 511 1.62 E-69

A-93 532.64 533 1.71 E-70

A-77 544.1 542/544 1.59 E-71

A-77 531.06 531 1.62 E-72

A-77 447.92 446/448 1.59 E-73

A-77 449.9 448/450 1.46 E-74

A-77 433.9 432/434 1.59 E-75

A-77 489.02 487/489 1.68 E-76

A-77 529.08 527/529 1.95 E-77

A-77 474.99 473/475 1.62 E-78

A-77 474.99 473/475 1.61 E-79

A-77 421.89 422 1.64 E-80

A-77 510.02 510/512 1.57 E-81

A-77 539.06 539 1.66 E-82

A-77 519 517/519 1.76 E-83

A-77 529.08 529 1.91 E-84

A-77 490.99 491 1.54 E-85

A-77 503 503 1.54 E-86

A-106 482.63 483 1.87 E-87

A-106 483.61 484 1.62 E-88

A-106 510.64 511 1.57 E-89

A-106 523.68 522 1.54 E-90

A-106 441.53 440 1.5 E-91

A-106 510.64 511 1.56 E-92

A-106 427.51 428 1.52 E-93

A-106 429.48 430 1.41 E-94

A-106 413.48 414 1.53 E-95

A-106 468.6 467 1.62 E-96

A-106 508.67 507 1.88 E-97

A-106 508.67 509 1.74 E-98

A-106 544.68 545 1.49 E-99

A-106 454.58 453 1.56 E-100

A-106 454.58 453 1.55 E-101

A-106 480.61 479 1.7 E-102

A-106 522.69 523 1.99 E-103

A-106 468.6 467 1.61 E-104

A-106 401.47 402 1.57 E-105

A-106 489.6 490 1.51 E-106

A-106 518.64 517 1.61 E-107

A-106 498.58 499 1.69 E-108

A-106 468.56 469 1.46 E-109

A-106 508.67 509 1.84 E-110

A-106 470.57 469 1.5 E-111

A-106 482.58 481 1.48 E-112

A-106 480.61 481 1.64 E-113

A-106 522.69 523 2.19 E-114

A-106 494.64 493 1.84 E-115

A-106 516.65 517 1.92 E-116

A-106 480.61 481 1.82 E-117

A-106 497.6 498 1.71 E-118

A-106 455.56 454 1.68 E-119

A-106 522.69 523 2.03 E-120

A-106 454.58 455 1.65 E-121

A-106 459.57 460 1.41 E-122

A-106 455.56 456 1.56 E-123

A-106 427.51 428 1.45 E-124

A-106 427.51 428 1.45 E-125

A-106 454.58 455 1.60 E-126

A-106 494.64 495 1.83 E-127

A-106 426.52 427 1.46 E-128

A-106 387.44 388 1.25 E-129

A-106 454.58 455 1.61 E-130

A-106 503.61 504 1.81 E-131

A-106 503.61 504 1.64 E-132

A-106 441.53 442 1.47 E-133

A-106 441.53 442 1.58 E-134

A-106 441.53 442 1.54 E-135

A-106 502.62 503 1.95 E-139

A-77 487 487/489 1.71 E-140

A-73 470.55 471 1.67 E-141

A-77 487 487/488 1.71 E-142

A-73 470.55 471 1.67 E-143

A-77 501.03 501/503 1.74 E-144

A-73 484.58 485 1.7 E-145

A-73 484.58 485 1.56 E-146

A-100 568.65 569 1.28 E-147

A-100 485.5 486 1.25 E-148

A-100 486.48 487 1.17 E-149

A-100 499.52 500 1.30 E-150

A-100 489.52 490 1.33 E-152

A-100 569.63 570 1.28 E-153

A-100 502.57 503 1.50 E-154

A-101 585.1 585/587 1.31 E-155

A-101 501.95 502/504 1.29 E-156

A-101 502.94 503/505 1.2 E-157

A-101 515.98 516 1.34 E-158

A-101 505.98 506 1.37 E-159

A-101 586.09 586 1.31 E-160

A-101 519.02 519 1.54 E-161

A-100 488.54 489 1.23 E-162

A-101 504.99 505/507 1.26 E-163

A-73 512.55 513 1.25 E-164

A-73 471.53 472 1.42 E-165

A-73 468.53 469 1.48 E-166

A-73 465.48 466 1.62 E-167

A-73 473.55 474 1.49 E-168

A-73 458.54 459 1.32 E-169

A-73 459.52 460 1.24 E-170

A-100 530.54 531 1.16 E-171

A-100 464.52 465 1.28 E-172

A-100 486.52 487 1.31 E-173

A-100 483.47 484 1.41 E-174

A-100 491.54 492 1.14 E-175

A-100 476.53 477 1.3 E-176

A-100 490.56 491 1.28 E-177

A-103 501.6 502 1.75 E-178

A-103 528.63 529 1.69 E-179

A-103 528.63 529 1.71 E-180

A-103 472.57 473 1.68 E-181

A-103 472.57 473 1.68 E-182

A-103 458.54 459 1.66 E-183

A-103 541.67 542 1.65 E-184

A-105 518.06 518 1.80 E-185

A-105 545.08 545 1.73 E-186

A-105 545.08 545 1.75 E-187

A-105 525 525 1.88 E-188

A-105 489.02 489 1.73 E-189

A-105 489.02 489 1.80 E-190

A-105 489.02 489 1.73 E-191

A-105 474.99 475 1.70 E-192

A-105 558.13 558 1.69 E-194

A-102 521.45 521/523/525 1.82 E-195

A-102 509.39 509 1.58 E-196

A-102 509.44 509/511/513 1.73 E-197

A-102 495.41 495 1.69 E-198

A-102 509.44 509/511/513 1.61 E-199

A-102 553.49 553/55/557 1.64 E-200

A-102 524.45 524 1.55 E-201

A-102 538.48 538 1.60 E-202

A-102 545.42 545/547/549 1.69 E-203

A-102 510.42 510 1.50 E-204

A-102 509.39 509 1.45 E-205

A -102 510.42 510/512/514 1.47 E-206

A-102 534.45 534 1.54 E-207

A-104 502.57 503 1.69 E-208

A-104 490.51 491 1.45 E-209

A-104 490.56 491 1.58 E-210

A-104 476.53 477 1.56 E-211

A-104 490.56 491 1.65 E-212

A-104 534.61 535 1.86 E-213

A-104 505.57 506 1.76 E-214

A-104 519.59 520 1.82 E-215

A-104 546.62 547 1.58 E-216

A-104 546.62 547 1.60 E-217

A-104 526.54 527 1.74 E-218

A-104 491.54 492 1.55 E-219

A-104 490.51 491 1.45 E-220

A-104 491.54 492 1.69 E-221

A-104 515.57 516 1.76 E-222

A-108 538.57 539 1.86 E-223

A-108 536.56 537 1.86 E-224

A-108 524.54 525 1.69 E-225

A-108 510.52 511 1.67 E-226

A-108 524.54 525 1.76 E-227

A-108 553.58 554 1.76 E-228

A-108 580.61 581 1.70 E-229

A-107 494.52 495 1.47 E-230

A-107 522.57 523 1.66 E-231

A-107 508.55 509 1.74 E-232

A-107 537.58 538 1.73 E-233

A-101 478.96 479 1.47 E-234

A-101 507.01 507 1.67 E-235

A-101 492.98 493 1.56 E-236

A-101 549.05 549 1.49 E-237

A-101 522.02 522 1.55 E-238

A-101 504.99 505/507 1.59 E-239

A-101 492.94 493 1.37 E-240

A-101 537.04 537/539 1.59 E-241

A-101 507.99 508/510 1.5 E-242

A-101 493.97 494 1.43 E-243

A-101 517.99 518 1.49 E-245

A-73 484.58 485 1.83 E-246

A-73 551.64 552 1.55 E-247

A-73 481.53 482 1.61 E-248

A-73 468.49 469 1.42 E-249

A-73 467.51 468 1.53 E-250

A-73 550.66 551 1.55 E-251

A-77 487 487 1.74 E-252

A-77 501.03 501 1.89 E-253

A-77 568.1 568 1.59 E-254

A-77 497.99 498 1.64 E-255

A-77 484.95 485 1.46 E-256

A-77 483.96 484 1.57 E-257

A-77 567.11 567 1.59 E-258

A-109 578.71 579 1.61 E-259

A-109 542.66 543 1.68 E-260

A-109 495.56 496 1.6 E-261

A-109 496.55 497 1.48 E-262

A-109 509.59 510 1.66 E-263

A-109 499.59 500 1.69 E-264

A-109 579.7 580 1.60 E-265

A-109 512.63 512 1.91 E-266

A-109 598.72 599 2.05 E-267

A-109 570.67 571 1.95 E-268

A-73 470.55 471 1.18 E-269

A-73 442.5 443 1.11 E-270

A-77 458.95 459 1.13 E-271

A-73 486.55 487 1.13 E-272

A-73 486.59 487 1.3 E-273

A-77 503 503 1.15 E-274

A-77 503.05 503 1.33 E-275

A-100 504.54 505 1.17 E-280

A-87 500.58 501 1.16 E-281

A-87 500.62 501 1.33 E-282

A-101 520.99 521 1.20 E-283

A-101 521.04 521 1.38 E-284

A-77 490.01 490/492 1.12 E-285

A-101 492.98 493 1.22 E-286

A-101 508 508 1.19 E-287

A-73 456.52 457 1.15 E-288

A-100 474.51 475 1.19 E-289

A-101 490.97 491 1.22 E-290

A-73 525.59 526 1.25 E-291

A-73 502.59 503 1.28 E-292

A-73 488.56 489 1.16 E-293

A-73 539.61 540 1.29 E-294

A-73 514.6 515 1.20 E-295

A-73 478.53 479 1.27 E-296

A-73 488.56 489 1.18 E-297

A-100 543.58 544 1.29 E-298

A-100 520.58 521 1.33 E-299

A-100 506.55 507 1.21 E-300

A-100 557.6 558 1.33 E-301

A-100 532.59 533 1.22 E-302

A-100 536.58 537 1.17 E-303

A-100 517.53 516 1.26 E-304

A-101 560.03 560 1.32 E-305

A-101 537.04 537 1.36 E-306

A-101 523.01 523 1.24 E-307

A-101 574.06 574 1.36 E-308

A-101 549.05 549 1.25 E-309

A-101 523.01 523 1.25 E-310

A-101 553.04 553 1.2 E-311

A-101 533.99 534/536 1.3 E-312

A-77 542.04 542/544 1.28 E-313

A-77 519.05 519 1.3 E-314

A-77 505.02 505 1.19 E-315

A-77 556.07 556/558 1.31 E-316

A-77 531.06 531/533 1.21 E-317

A-77 505.02 505 1.21 E-318

A-77 535.04 535/537 1.16 E-319

A-73 584.69 585 1.46 E-320

A-73 484.58 485 1.19 E-321

A-73 600.69 601 1.43 E-322

A-73 500.58 501 1.15 E-323

A-73 556.64 557 1.40 E-324

A-73 456.52 457 1.12 E-325

A-73 600.69 601 1.45 E-326

A-73 500.58 501 1.15 E-327

A-73 584.69 585 1.46 E-328

A-73 484.58 485 1.18 E-329

A-73 556.64 557 1.38 E-330

A-73 456.52 457 1.12 E-331

A-73 556.64 557 1.38 E-332

A-73 456.52 457 1.14 E-333

A-102 507.42 507/509/511 1.26 E-334

A-77 472.98 473/475 1.19 E-335

A-102 535.48 535 1.35 E-336

A-100 502.57 503 1.28 E-337

A-101 519.02 519 1.32 E-338

A-77 501.03 501/503 1.28 E-339

A-73 484.58 485 1.25 E-340

A-100 476.53 477 1.36 E-341

A-101 492.98 493/495 1.35 E-342

A-77 529 529/531 1.24 E-343

A-77 474.99 475 1.28 E-344

A-77 474.99 475 1.28 E-345

A-73 518.59 519 1.15 E-346

A-73 512.55 513 1.20 E-347

A-73 458.54 459 1.25 E-348

A-73 458.54 459 1.25 E-349

A-73 502.59 503 1.27

TABLE 5 Biological Data of Examples C-1 to C-50 Nr. IC₅₀ mTOR [nM] IC₅₀PI3K [nM] C-01 24 26 C-02 24 24 C-03 11 40 C-04 8 29 C-05 3 50 C-06 5 86C-07 30 39 C-08 8 65 C-09 6 254 C-10 17 401 C-11 2 47 C-12 5 71 C-13 6499 C-14 18 66 C-15 20 189 C-15A 2 57 C-16 18 236 C-17 69 99 C-18 29 137C-19 19 222 C-20 40 58 C-21 44 99 C-22 76 30 C-23 63 78 C-24 34 59 C-25163 64 C-26 57 43 C-27 20 57 C-28 50 58 C-29 34 24 C-30 51 40 C-31 22 30C-32 41 32 C-33 34 61 C-34 79 37 C-35 32 29 C-36 82 308 C-37 90 224 C-3824 68 C-39 13 380 C-40 4 459 C-41 14 539 C-42 13 309 C-43 32 184 C-44109 188 C-45 4 194 C-46 31 226 C-47 17 541 C-48 28 596 C-49 31 67 C-5044 72

TABLE 6 Biological Data for Examples D1-D240 Nr. IC₅₀ mTOR [nM] IC₅₀PI3K [nM] D-1 3 78 D-2 30 402 D-3 33 574 D-4 1 58 D-5 8 225 D-6 2 135D-7 2 103 D-8 2 215 D-9 33 591 D-10 4 206 D-11 2 109 D-12 3 163 D-13 4312 D-14 27 647 D-15 3 215 D-16 5 192 D-17 7 178 D-18 8 481 D-19 9 92D-20 8 116 D-21 8 270 D-22 68 1269 D-23 2 123 D-24 9 1017 D-25 26 498D-26 7 552 D-27 5 370 D-28 0.99 65 D-29 1 162 D-30 3 68 D-31 0.88 97D-32 0.74 121 D-33 3 181 D-34 1 36 D-35 2 63 D-36 0.6 84 D-37 3 118 D-384 366 D-39 5 89 D-40 18 499 D-41 2 177 D-42 0.84 246 D-43 2 436 D-440.82 27 D-45 2 186 D-46 2 97 D-47 2 63 D-48 3 251 D-49 2 60 D-50 2 211D-51 1 121 D-52 1 134 D-53 3 213 D-54 4 81 D-55 2 36 D-56 2 73 D-57 3152 D-58 2 217 D-59 1 19 D-60 8 546 D-61 1 86 D-62 3 205 D-63 2 234 D-642 198 D-65 30 436 D-66 2 110 D-67 2 244 D-68 4 42 D-69 3 133 D-70 5 490D-71 1 85 D-73 24 324 D-74 33 630 D-75 33 335 D-76 13 339 D-77 28 303D-78 5 305 D-79 1 170 D-80 5 68 D-81 4 84 D-82 4 146 D-83 4 219 D-84 3127 D-85 7 115 D-86 4 95 D-87 7 233 D-88 4 118 D-89 5 52 D-90 6 62 D-914 109 D-92 7 124 D-93 7 266 D-94 39 1825 D-95 6 145 D-96 6 151 D-97 12476 D-98 10 199 D-99 16 452 D-100 16 347 D-101 2 49 D-103 28 470 D-104 6125 D-105 3 46 D-106 5 249 D-107 9 82 D-108 13 313 D-110 6 64 D-111 24359 D-112 17 323 D-113 13 57 D-114 12 188 D-116 16 129 D-117 8 27 D-11817 404 D-119 14 55 D-120 9 108 D-121 3 127 D-122 6 198 D-123 17 324D-124 7 228 D-125 4 269 D-126 8 142 D-127 13 344 D-128 8 157 D-129 10392 D-130 16 384 D-131 5 119 D-132 26 184 D-133 2 115 D-134 21 333 D-1353 136 D-136 5 228 D-138 5 101 D-139 7 374 D-140 57 510 D-141 3 64 D-1426 94 D-143 6 77 D-145 2 58 D-146 4 66 D-147 3 65 D-148 43 420 D-149 30433 D-150 20 177 D-151 10 467 D-152 8 164 D-153 17 67 D-154 22 405 D-15510 209 D-156 3 53 D-157 5 65 D-159 7 66 D-160 29 658 D-161 7 D-162 7D-163 12 D-164 12 D-165 12 D-166 6 D-167 7 D-168 9 D-169 88 D-170 75D-172 7 D-173 62 D-174 34 D-175 21 D-176 50 D-177 33 D-178 6 D-179 5D-180 20 D-181 32 D-182 22 D-183 16 D-185 16 D-186 7 D-187 7 D-188 4 67D-189 3 118 D-190 8 153 D-191 17 81 D-192 4 134 D-193 3 65 D-194 3 106D-195 4 125 D-196 19 292 D-197 31 280 D-198 3 203 D-199 15 347 D-200 46566 D-201 11 134 D-202 16 413 D-203 1 57 D-204 2 69 D-205 28 335 D-20613 351 D-207 10 436 D-208 8 308 D-209 11 158 D-210 7 370 D-211 5 46D-212 5 79 D-213 18 272 D-214 1 72 D-215 2 227 D-216 1 59 D-217 4 44D-218 5 80 D-219 11 105 D-220 7 64 D-221 7 63 D-222 10 42 D-223 13 77D-224 12 39 D-225 16 66 D-226 10 48 D-227 17 47 D-228 8 52 D-229 12 65D-230 15 37 D-231 22 46 D-232 9 38 D-233 17 45 D-234 8 156 D-235 17 226D-236 8 269 D-237 18 161 D-238 25 382 D-239 3 55 D-240 24 214

TABLE 7 Biological Data for Examples E-1-E-349 IC₅₀ mTOR IC₅₀ PI3K EC₅₀BT474 EC₅₀ U87MG Nr. [nM] [nM] [nM] [nM] E-1 1.29 132.4 18.19 46.87 E-22.18 237.3 45.25 E-3 2.24 275.8 14.67 47.13 E-4 2.14 133.4 27.34 75.29E-5 2.15 78.8 27.46 49.43 E-6 0.35 123.8 24.89 E-7 0.94 189.1 16.41131.1 E-8 7.52 1325 84.01 E-9 0.4 199.4 9.76 13.03 E-10 2.49 49.06 48.69E-11 0.94 124.8 79.82 E-12 3.42 65 89.94 E-13 3.79 154.1 85.29 E-14 1.02352.7 16.58 58.69 E-15 8.89 108.2 64.15 E-16 20.91 333.2 124.9 E-17 3.4135.9 96.53 E-18 5.41 228.2 42.04 E-19 8.74 90.45 30.32 30.31 E-20 4.5100.6 55.29 E-21 6.99 374.3 77.58 E-22 56.51 509.7 224.9 E-23 2.5 63.5942.97 E-24 6.2 93.52 57.8 E-25 5.9 76.79 57.33 E-26 32.11 497.6 338.1E-27 1.99 58.28 148.9 E-28 3.94 65.6 229.1 E-29 3.14 65.05 69.6 E-3042.96 420.1 186.1 E-31 29.7 432.9 243.6 E-32 19.76 176.5 231.5 E-3318.68 467.3 202.3 E-34 7.85 163.5 174 E-35 16.87 67.44 134.5 E-36 22.18405.2 254.8 E-37 9.65 208.8 117.2 E-38 2.8 52.89 137.2 E-39 4.57 65.3275.62 E-40 40.09 513.8 373 E-41 6.99 66 77.98 E-42 29.33 658 247.8 E-434.52 501.7 206.6 E-44 11.35 232.2 199.7 E-45 10.2 96.86 448 E-46 11.86104.2 186.1 E-47 12.48 146.4 192.2 E-48 6.34 100.3 159.6 E-49 6.64 74.541063 E-50 8.86 156.9 148.6 E-51 88.48 205.4 E-52 75.07 578.1 E-53 51.12460.3 794.7 E-54 7.24 165 514.6 E-55 61.95 148.4 E-56 33.76 357 451.6E-57 20.94 279.5 201.5 E-58 50.49 253.2 449.6 E-59 33.19 294.4 481 E-606.43 69.38 124.3 E-61 4.84 102.7 243.5 E-62 19.5 246.1 268.7 E-63 32.4342.9 352.9 E-64 21.85 118.4 225.6 E-65 15.76 88 444.4 E-66 53.75 661.6715.5 E-67 15.89 3052 3296 E-68 6.82 411.5 151 E-69 4.95 415.3 531.5E-70 1.18 136.6 28.55 74.86 E-71 1.09 99.86 35.36 E-72 0.46 66.47 102.1E-73 0.8 88.29 242.9 E-74 0.27 53.88 102 E-75 12.36 274.8 299.4 E-761.78 232.8 100.2 E-77 2.87 129.2 115.6 E-78 3.38 232 167.2 E-79 1.3749.97 77.94 E-80 2.64 48.19 112.8 E-81 0.36 39.47 34.32 E-82 3.59 81.71107.8 E-83 6 465.5 64.41 E-84 3.8 113.4 68.43 E-85 4.4 56.4 280.3 E-861.52 147 90.18 E-87 3.64 78.85 146.9 E-88 1.57 84.39 47.65 E-89 4.84 307222 E-90 2.69 52.47 164.9 E-91 3.43 178.6 132.4 E-92 2.79 59.45 122.6E-93 1.82 106.9 152 E-94 2.42 145.6 119.3 E-95 12.84 173.1 267.4 E-9610.41 199.8 124.8 E-97 14.54 366.8 289.8 E-98 1.41 160.2 121.1 E-9911.05 190.5 270.3 E-101 1.78 114.6 81.85 E-102 7.8 289.2 108.8 E-10311.54 232.1 209.8 E-104 3.23 71.94 104.3 E-105 2.87 51.68 144.6 E-1060.92 36.82 44.26 E-107 2.48 62.89 117 E-108 2.68 71.52 143.1 E-109 9.66259 82.8 E-110 3.5 82.31 140.6 E-111 5.98 31.84 266.8 E-112 15.32 248.6336.2 E-113 4.51 413.5 356.4 E-114 1.23 90.69 47.43 E-115 1.83 153.6152.9 E-116 6.82 110 18.58 E-117 11.03 73.48 26.69 E-118 5.09 67.8530.89 E-119 10.94 281.1 44.96 E-120 73.02 349.3 E-121 3.43 63.89 53.62E-122 5.86 62.81 55.69 E-123 6.62 46.61 114.5 E-124 8.91 53.3 141 E-12528.7 160.8 101.2 E-126 24.16 194.7 88.96 E-127 11.91 158.3 67.76 E-12813.88 37.16 55.15 E-129 27.44 237.1 86.45 E-130 14.3 69.07 33.32 E-13117.09 158.3 82.7 E-132 9.55 45.55 69.67 E-133 6.85 77.85 43.11 E-1344.16 44.88 34.75 E-135 16.74 149.1 59.12 E-139 3.15 160.2 74.2 E-1400.99 198.5 13.72 39.16 E-141 1.69 259.8 33.14 E-142 1.5 107.4 16.1418.79 E-143 1.15 126.7 22.39 E-144 2.98 169.2 17.58 E-145 5.45 358.348.31 E-146 0.73 45.78 11.91 E-147 0.54 55.7 13.79 E-148 1.36 70.64 33.5E-149 0.89 85.79 32.81 E-150 1.75 120.1 20.22 E-152 0.88 67.85 17.75E-153 0.89 212.7 14.25 E-154 0.7 30.2 18.68 E-155 0.71 15.47 23.72 E-1560.51 18.28 12.09 E-157 0.59 37.51 18.28 E-158 2.22 122.3 22.58 E-1590.53 25.82 19.68 E-160 1.88 114.7 114 E-161 13.63 924.7 236.6 E-162 10.4539.9 208.4 E-163 1.71 50.82 E-164 2.22 154.2 22.17 E-165 1.47 178.318.59 E-166 2.49 153.8 28.84 E-167 21.06 156.8 E-168 66.44 373.2 E-1696.8 69.98 E-170 1.56 96.52 25.69 E-171 23.12 358.1 E-172 2.11 268.332.11 E-173 8.6 163.9 39.71 E-174 18.75 164.7 141.5 E-175 17.16 163.3575.9 E-176 39.16 490.6 E-177 4.63 337.4 57.04 E-178 5.19 335 47.1 E-1793.11 275.9 28.72 E-180 5.43 357.4 67.05 E-181 8.83 275.3 93.82 E-1822.44 246.7 54.51 E-183 4.7 308.1 104.2 E-184 2.81 399.4 39.78 E-185 3.43201.5 25.91 E-186 0.68 325.3 22.36 E-187 1.93 161.5 29.84 E-188 4.69355.6 77.53 E-189 1.6 186.4 44.78 E-190 19.97 175.4 82.41 E-191 5.16141.5 45.04 E-192 2.86 333.7 52.68 E-193 276.6 183.8 E-194 0.87 129.325.06 E-195 1.99 20.33 E-196 5.28 234.7 45.59 E-197 3.78 122.8 16.37E-198 1.4 90.89 9.84 E-199 1.34 74.6 9.81 E-200 1.11 58.79 9.82 E-2011.62 98.1 9.77 E-202 2.27 85.82 14.19 E-203 3.29 95.16 14.93 E-204 3.92138.2 54.62 E-205 0.59 48.89 20.15 E-206 1.38 71.77 12.14 E-207 2.51581.2 58.69 E-208 2.87 175.6 40.36 E-209 5.71 545.6 80.73 E-210 2.84388.1 59.39 E-211 3.58 472.3 96.74 E-212 2.3 645 72.36 E-213 1.51 465.155.13 E-214 3.49 599.9 84.08 E-215 1.96 423.3 48 E-216 2.14 465.9 38.33E-217 7.56 326.6 47.96 E-218 4.69 361.8 57.39 E-219 3.2 163 37.33 E-2204.33 292.6 33.86 E-221 2.21 212.8 33.7 E-222 21.17 530.1 E-223 9.33 15766.44 E-224 55.47 401.8 E-225 14.07 223.7 E-226 14.41 195.6 E-227 13.28267.2 E-228 27.93 356.5 E-229 8.85 173.8 48.64 E-230 2.72 278.9 45.26E-231 13.62 184.7 E-232 11.52 142.4 E-233 1 89.79 23.04 E-234 0.67 263.221.66 E-235 1.24 178.2 19.16 E-236 0.64 141.3 18.75 E-237 0.96 120.720.61 E-238 0.07 174.6 19.07 E-239 0.26 46.18 15.16 E-240 0.29 115.416.84 E-241 0.25 91.52 16.6 E-242 0.2 120.1 18.37 E-243 0.73 109.7 29.82E-245 0.47 288.2 21.05 E-246 1.13 81.31 61.41 E-247 0.8 95.37 19.59E-248 1.18 50.79 56.1 E-249 1.75 60.47 22.83 E-250 4.36 92.16 37.88E-251 7.99 90.72 588.1 E-252 0.57 48.24 15.22 E-253 1.47 30.6 64.56E-254 0.97 31.55 16.6 E-255 0.46 4.83 43.05 E-256 0.67 22.96 27.94 E-2572.7 58.26 43.95 E-258 1.55 110.2 13.1 E-259 1.61 209.2 13.93 E-260 0.8163.84 22.95 E-261 1.46 44.34 11.44 E-262 1.63 133.7 18.79 E-263 2.09204.4 22.85 E-264 1.39 61.64 32.3 E-265 1.64 205.6 24.34 E-266 11.46560.2 273.2 E-267 9.26 420.9 168.9 E-268 10.44 242.1 437.7 E-269 15.21251.8 59.7 E-270 13.23 328.4 213 E-271 2.75 113.1 10.3 E-272 24.53 475.3107 E-273 4.24 119.3 14.14 E-274 39.77 444.9 E-275 3.07 140.8 15.5 E-28016.96 153.4 36.65 E-281 144.8 679 E-282 3.83 173.4 8.61 E-283 40.26446.5 E-284 8.45 180.8 77.83 E-285 13.91 646.9 12.42 E-286 6.76 526.729.35 E-287 9.81 288.4 523 E-288 3.8 342.9 115.5 E-289 5.54 297.9 71.42E-290 1.51 200.4 14.86 E-291 2.7 219.8 18.17 E-292 1.26 212 20.26 E-2931.53 168.1 31.3 E-294 0.68 137.2 11.15 E-295 1.09 109.4 15.1 E-296 1.56121.5 18.51 E-297 0.21 208.16 E-298 0.56 187 E-299 0.58 159.65 E-3000.49 783.3 E-301 0.28 106.03 E-302 1.66 112.89 E-303 2.11 144.41 E-3041.26 108.17 E-305 0.68 110.06 E-306 1.01 108.46 E-307 0.45 192.99 E-3080.32 63.43 E-309 0.56 239.33 E-310 0.76 86.05 E-311 0.52 69.07 E-3120.39 110.31 E-313 0.92 121.81 E-314 1.68 76.12 E-315 1.5 126.66 E-3161.29 57.12 E-317 2.23 92.8 E-318 1.28 107.46 E-319 9.74 359.57 E-3205.95 1301.49 E-321 8.92 412.25 E-322 6.48 390.88 E-323 9.67 841.74 E-32413.61 935.07 E-325 67.77 1175.43 E-326 11.42 367.08 E-327 7.08 1356.31E-328 25.52 585.88 E-329 4.43 237.84 E-330 32.58 600.97 E-331 5 150.52E-332 26.53 655.45 E-333 9.74 599.13 E-334 6.07 966 E-335 10.6 2212.26E-336 5.21 773.45 E-337 10.07 862.37 E-338 4.85 634.33 E-339 7.04 330.81E-340 5.86 364.04 E-341 4.36 281.99 E-342 0.66 137.31 E-343 5.62 148.58E-344 2.84 149.4 E-345 1.15 109.07 E-346 0.45 167.33 E-347 3.42 205.14E-348 5.46 143.82 E-349 1.03 175.45

Analytical Method 1

HPLC: Agilent 1100 Series MS: Agilent LC/MSD SL column: Phenomenex,Mercury Gemini C18, 3 μm, 2.0 × 20 mm, Part. No. 00M-4439-B0-CE solventA: 5 mM NH₄HCO₃/20 mM NH₃ B: acetonitrile HPLC grade detection: MS:Positive and negative mass rang: 120-700 m/z fragmentor: 70 gain EMV:  1threshold:  0.25 UV: 315 nm bandwidth: 170 nm reference: off range:210-400 nm range step: 2.00 nm peakwidth: <0.01 min slit: 2 nminjection: 5 μL flow: 1.00 mL/min column temperature: 40° C. gradient:0.00 min 5% B 0.00-2.50 min 5% -> 95% B 2.50-2.80 min 95% B 2.81-3.10min 95% -> 5% B

Analytical Method 2

Instrument: Agilent 1100-SL: incl. ELSD/DAD/MSD

Chromatography:

-   -   Column: Phenomenex Gemini® C18, 50×2.0 mm, 3μ

Method “Acid”

-   -   Eluent A: 0.1% formic acid in acetonitrile    -   Eluent B: 0.1% formic acid in Water    -   Linear Gradient program: t₀=2% A, t_(3.5min)=98% A, t_(6min)=98%        A    -   Flow: 1 mL/min    -   Column oven temperature: 35° C.

Method “Base”

-   -   Eluent A: 10 mM ammonia in acetonitrile    -   Eluent B: 10 mM ammonia in water    -   Linear Gradient program: t₀=2% A, t_(3.5min)=98% A, t_(6min)=98%        A    -   Flow: 1 mL/min    -   Column oven temperature: 35° C.

Evaporative Light Scattering Detector (ELSD):

-   -   Instrument: Polymer Laboratories PL-ELS 2100    -   Nebuliser gas flow: 1.1 L/min N₂    -   Nebuliser temp: 50° C.    -   Evaporation temp: 80° C.    -   Lamp: Blue LED 480 nm

Diode Array Detector (DAD):

-   -   Instrument: Agilent G1316A    -   Sample wavelength: 220-320 nm    -   Reference wavelength: Off

Mass Spectroscopy (MSD):

-   -   Instrument: Agilent LC/MSD-SL    -   Ionisation: ESI (Positive & Negative)    -   Mass range: 100-800

Abbreviations Used

ACN acetonitrile min minute(s) bu butyl mL millilitre CDI carbonyldiimidazole MS mass spectrometry d day(s) N normal DC thin layerchromatography NIS N-iodosuccinimide DCM dichloromethane NMPN-methylpyrrolindinone DIPEA diisopropylethyl amine NMR nuclearresonance spectroscopy DME dimethylether NP normal phase DMFN,N-dimethylformamide ppm part per million DMSO dimethylsulphoxide R_(f)retention factor eq. equivalent RP reversed phase EtOH ethanol preppreparative h hour(s) RT room temperature HPLC high performance liquidtert tertiary chromatography LC liquid chromatography t_(R) retentiontime M molar THF tetrahydrofuran MeOH methanol TMS TetramethylsilanylInt. Intermediate PI3Ka PI3Kalpha or PI3Kα LDA LithiumdiisopropylamineDIA Diisopropylamine PE Petrolether TLC Thin layer chromatography EtOAcEthylacetate Pd(dppf)Cl₂ [1,1- Bis(diphenylphosphino)-ferrocene]dichloropalladium(II)] [Ir(COD)(OMe)]₂ (1,5- Pin2B2Bis(pinacolato)diboron Cyclooctadiene)(methoxy)iridium(I) dimer

The Examples that follow describe the biological activity of thecompounds according to the invention without restricting the inventionto these Examples. All the EC₅₀ and IC₅₀ values listed herein areindicated in nM (nanomoles).

mTOR Kinase Activity Assay(Phosphorylation Status of mTOR Substrate 4E-BP1; TR-FRET)

mTOR assay described herein provides IC50 values indicating the activityof the compounds inhibiting mTOR activity. Inhibition of mTOR isexpected to be indicative of activity in treating conditions ofexcessive or anomalous cell proliferation such as cancer.

Assay Principle:

The mTOR kinase TR-FRET assay utilizes a physiologically relevantprotein substrate for mTOR (4E-BP1, labeled with an acceptor fluorophore(Green Fluorescent Protein) and paired with a corresponding Tb-labeledphospho-specific antibody.

The assay itself can be divided into two phases: the reaction phase andthe detection phase. In the reaction phase, all components required forthe kinase reaction are added to the well, including the labeled proteinsubstrate. The reaction is allowed to incubate for 60 minutes. After thereaction, EDTA is added to stop the kinase reaction, and terbium-labeledantibody is added to bind phosphorylated product. Because the terbiumchelate is stable at the EDTA concentrations used to stop a kinaseassay, the antibody and EDTA can be pre-mixed prior to addition tominimize pipetting steps. Binding of the terbium labeled antibody to thefluorophore-labeled phosphorylated product brings the terbium and GFPinto proximity, resulting in an increase in TR-FRET. In the presence ofan inhibitor, formation of phosphorylated product is reduced, and theTR-FRET value is decreased.

Materials:

-   -   GFP-4E-BP1 substrate; Invitrogen order no. PV4759,    -   Lanthascreen Tb-anti-p4E-BP1 (pThr46) Antibody Kit; Invitrogen        order no. PV4758,    -   FRAP1 (mTOR) kinase; Invitrogen order no. PV4753,    -   ATP 10 mM    -   5× Assay Buffer (250 mM HEPES pH7.5, 0.05% Polysorbate 20, 5 mM        EGTA, 50 mM MnCl2)    -   EDTA 500 mM

Determining IC₅₀ Values for Test Compounds: Kinase Reaction Conditions

400 nM GFP-4E-BP1, 8 M ATP, ˜150 ng/mL mTOR, 50 mM HEPES

pH 7.5, 0.01% Polysorbate 20, 1 mM EGTA, 10 mM MnCl2, and variableamounts of test compounds.

Preparation of Reagents Note:

Thaw and keep mTOR, the substrate, ATP, and the antibody on ice prior tomaking working dilutions. Working dilutions of these components can bekept at room temperature for short periods of time the day of use.

1. Add 2 ml of 5× Assay Buffer to 8 ml water to prepare 10 ml of 1×Assay Buffer, wherein the concentration of 1× Assay Buffer is 50 mMHEPES pH 7.5, 0.01% Polysorbate 20, 1 mM EGTA, and 10 mM MnCl2.

2. Prepare Antibody/EDTA Solution by first adding 2.75 μl of Tb-antip4E-BP1 Antibody to 2397 μl of LanthaScreen™ TR-FRET Dilution Buffer.Then, add 100 μl of 0.5 M EDTA.

3. Prepare 4× Substrate/Enzyme Solution by first adding 72 μl ofGFP-4E-BP1 (22 M) to 926 μl of 1× Assay Buffer. Then, add 1.6 μl of mTOR(0.45 mg/mL).

4. Prepare ATP Solution by adding 3.2 μl of 10 mM ATP to 1997 μl of 1×Assay Buffer.

Serial Dilution of Inhibitors (16 Point Curve)

Inhibitors are serially diluted in DMSO, then diluted to a 4× workingconcentration with 1× Assay Buffer.

1. Dispense 40 μl of DMSO to two adjacent columns of a 96 well plate percompound (e.g. columns 1 and 2).

2. Add 10 μl of inhibitor stock (10 mM) to the first well of the firstcolumn (A1) and mix.

3. Remove 10 μl from A1 and transfer to the adjacent well in the nextcolumn (B1) and mix.

4. Remove 10 μl from B1 and transfer to the next well in the firstcolumn (B2) and mix.

5. Repeat this dilution pattern through well H1 and leave the last well(H2) as DMSO only.

6. Remove 4 μl of diluted compounds and add to 96 μl of 1× Assay Bufferin a 96-well plate making 4× compound dilutions.

Kinase Reaction

1. Add 2.5 μl of 4× compound dilutions to a 384-well plate.

2. Add 2.5 μl of 4× Enzyme/Substrate Solution.

4. Preincubate for 30 min. at RT (shaker).

5. Add 5 μl of ATP Solution to all wells to start reactions.

6. Shake the assay plate on a plate shaker for 30 seconds.

7. Incubate the assay plate for one hour at room temperature (20-25°C.).

Stop Step and Fluorescence Detection

1. Add 10 μl of Antibody/EDTA Solution to each well in columns 1-9.

2. Shake the assay plate on a plate shaker for 30 seconds.

3. Incubate the assay plate for one hour at room temperature (20-25°C.).

4. Measure the GFP (FRET) and terbium (reference) emission signals on afluorescence plate reader (e.g. Perkin Elmer Envision).

Data Analysis

1. Calculate the emission ratio for each sample by dividing the GFP(FRET) signal by the terbium (reference) signal.

2. Plot the concentration of each compound versus the emission ratio.Determine the concentration of compound required to reach 50% of themaximum signal (IC50). Determination of IC50 values can be obtained bycurve fitting (sigmoidal dose response, variable slope) using Prismsoftware from GraphPad).

Inhibition of PI3Kalpha-Induced PIP-2 Phosphorylation

PI3Kalpha assay described herein provides IC₅₀ values indicating theactivity of the compounds inhibiting PI3 kinase alpha activity.Inhibition of PI3 kinase is expected to be indicative of activity intreating conditions of excessive or anomalous cell proliferation, suchas cancers. See also J. A. Engelman, Nature Reviews Cancer, 2009, 9,550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8, 627-64.

Method type: Filter-Binding-Assay

1. Materials

Assay buffer: 40 mM HEPES pH 7.5 SIGMA H-3375

-   -   100 mM NaCl Merck 1.064.041.000    -   1 mM EGTA SIGMA E-4378    -   1 mM β-Glycerophosphate SIGMA G-6253    -   7 mM MgCl2 Merck 58.331.000    -   1 mM DTT SIGMA D-0632    -   (0.1% BSA only during preparation of Lipidmix after        ultrasonication) Phospholipid blend mix (═substrate) from Avanti        Polar Lipids (#790770):

Phosphatidylinositol-4,5-biphosphate (#840046) 3.665%

-   -   Phosphatidylethanolamine (#83022) 39.26%    -   Phosphatidylserine (#830032) 36.66%    -   Sphingomyeline (#860062) 3.665%    -   Phosphatidylcholine (#830053) 16.75%    -   Per aliquot lipid (16.6 mg): 26 ml assay buffer+520 μl BSA (5%)

PI3 Kinase alpha is expressed in SF9 insect cells, coinfected withviruses encoding p85alpha and His-p110alpha, purified by combinedNi-affinity and anion exchange chromatography). Aliquoted in desiredamounts and stored at −80° C. Final assay concentration 25 ng/wellPhosphotyrosin PDGFRbeta-peptide H-CGG-pY-MDMSKDESVD-pY-VPMLDM-NH2 wassynthesized by Jerini Peptide Technologies (JPT) and used in a finalconc. of 1.7 μM (stock 100 μM prepared in Assay buffer with DTT,aliquoted in desired amounts and stored at −80° C.)

Cold ATP (from Sigma; A-7699), 100 μM stocksolution in H2O, use 1 μMfinal concentration in assay

[33P]-ATP, 370 MBq/ml from Amersham (#AH9968), use 0.5 μCi/well (10mCi/ml)

Clear 96-well plates from Greiner (#655 162)

Filter plates: Perkin Elmer UniFilter GF/B #6005177

Microscint 0 (from Perkin Elmer, #6013611)

2. Assay Procedure

The substrate-containing lipid vesicles are dissolved to a concentrationof 0.637 mg lipid blend/ml assay buffer (with BSA, freshly added) in 50ml Falcon->keep on ice, followed by ultrasonication (pulse of 15 secfollowed by a pause of 10 sec, 4×). Compounds are serially diluted inassay buffer+6% DMSO and 10 μl of each dilution is added per well of a96-well plate (compounds are tested in duplicates) and mixed with 30 μlof the lipid vesicles containing PDGFR-Peptide (0.5 μM final) and PI3Kalpha (25 ng/well final). The mixture is then incubated for 20 minutesat room temperature. Subsequently, 20 μl of assay buffer containing 3 μMcold ATP and 0.5 μCi/20 μl 33P-ATP are added. The plates are thenincubated at room temperature for 120 minutes (shaking with 300 rpm).The reaction mix is transferred onto filter plates using “filtermateharvester” from Packard: filter plates are rinsed with PBS, then thereaction mix is filtered onto the filter plate, washed times with PBSand are allowed to dry for 30-60 minutes at 50° C.

The plate bottom is sealed with Perkin Elmer white adhesive foil and 25μl/well Microscint0 are added, the top is covered with transparentadhesive foil and the plate is measured with Wallac Trilux 1450Microbeta Counter.

As positive control serve wells containing vehicle controls (1% DMSO inassay buffer), showing non-inhibited kinase activity (high values).Wells containing assay buffer instead of enzyme can serve as control forbackground activity (low values).

3. Evaluation

Calculate IC₅₀ values using the Smiley program (based on GrapPad Prism)

PC3 Proliferation Test

The test is based on measurement of cellular DNA content via fluorescentdye binding. Because cellular DNA content is highly regulated, it isclosely proportional to cell number. The extent of proliferation isdetermined by comparing cell counts for samples treated with drugs withuntreated controls.

PC3 (human prostate carcinoma cell line) cells are sown in microtitreplates and incubated overnight in culture medium at 37° C. and 5% CO₂.The test substances are diluted stepwise and added to the cells suchthat the total volume is 200 μL/well. Cells to which diluent, but notsubstance, is added serve as controls. After an incubation time of 3days, the medium is replaced by 100 μL/well dye-binding solution and thecells are incubated at 37° C. in the dark for a further 60 min. Formeasuring the fluorescence, excitation takes place at a wavelength of485 nm and the emission is measured at 530 nm. EC₅₀ values arecalculated using the GraphPad Prism program.

AlamarBlue Assay in AN3 CA Cells

The alamarBlue cell assay provides EC₅₀ values indicative of theantiproliferative or cytotoxic effects of the compounds on the AN3 CAhuman endometrial cancer cell line.

1. Description

alamarBlue® is designed to provide a rapid and sensitive measure of cellproliferation and cytotoxicity in various human and animal cell lines.The assay is based on the reduction of alamarBlue in the reducingenvironment of living (metabolically active) cells. In the presence ofadded cytotoxic or antiproliferative compounds, the innate metabolicactivity ceases.

AlamarBlue is soluble and stable in culture medium. Measurements aremade fluorometrically by exciting at 530-560 nm and measuring emissionat 590 nm. In reporting percent alamarBlue reduction by monitoringfluorescence, data are expressed as fluorescence emission intensityunits as a function of time of incubation.

2. Cells and Reagents

AN3 CA cells Human endometrial cancer cells (ATCC HTB-111) alamarBlueSerotec Ltd PBS (w/o Ca, Mg) Life Technologies, Gibco BRL (Cat. No.4190-094) DMEM Medium Lonza (Cat. No. BE-12-604F) Fetal calf serum LifeTechnologies, Gibco BRL (Cat. No. 10270-106)

3. Equipment

-   -   96-well plates, flat bottom (Falcon, Cat. No.: 353072)    -   96-well plates, U-shaped (Costar, Cat. No.: 3799)    -   CO₂—Incubator    -   Microplate Reader, Spectramax Plus, Molecular Devices

4. Typical Procedure

-   Day 0: Seed 3000 AN3 CA cells (DMEM/10% FCS) in 180 μl medium into a    96-well plate, flat bottom (include medium blank). Incubate plates    at 37° C. in a CO₂ incubator overnight.-   Day 1: Dilute compounds to a concentration 100 μM->1:5, 10 dilution    steps, in 96-well plates.    -   Add 20 μl per well of each dilution to cells (total volume per        well 200 μl; final conc. of cpds: 10 μM->1:5; 0.5% DMSO final).        If required, test further dilutions.    -   All concentrations are tested in duplicates.    -   Controls: Cells w/o cpd. (+20 μl medium/DMSO).    -   Cells are incubated with compounds for 3 days.-   Day 4: Add 25 μl of alamarBlue solution to each well and incubate    for 5-8 hours at 37° C. Measure fluorescence by exciting at 530-560    nm and measuring emission at 590 nm.

5. Evaluation

-   -   Calculate EC₅₀ using GraphPad Prism (Fifty).

alamarBlue® assay can be used to measure the inhibition of mTOR as wellas PI3Kalpha in vitro.

CyQuant Assay in U87MG Cells

The CyQuant assay provides EC₅₀ values indicative of theantiproliferative or cytotoxic effects of the compounds on the U87MGhuman glioblastoma cell line.

1. Description

The test is based on measurement of cellular DNA content via fluorescentdye binding.

Because cellular DNA content is highly regulated, it is closelyproportional to cell number.

The extent of proliferation is determined by comparing cell counts forsamples treated with drugs with untreated controls. In the assay, aDNA-binding dye in combination with a plasma membrane permeabilizationreagent is used. The medium is aspirated, replaced with dye bindingsolution, cells are incubated for 30-60 min., then fluorescence ismeasured (excitation at 485 nm, emission detection at 530 nm). Data areexpressed as fluorescence emission intensity units as a function of timeof incubation.

2. Cells and Reagents

U-87MG cells Human glioblastoma cells (ATCC HTB-14) CyQuant NF assayInvitrogen Cat.# C35006 PBS (w/o Ca, Mg) Life Technologies, Gibco BRL(Cat. No. 4190-094) RPMI1640 Medium Life Technologies, Gibco BRL (Cat.No. 61870-010) Fetal calf serum Life Technologies, Gibco BRL (Cat. No.10270-106)

3. Equipment

-   -   96-well plates, flat bottom (Falcon, Cat. No.: 353072)    -   96-well plates, U-shaped (Costar, Cat. No.: 3799)    -   CO₂—Incubator    -   Microplate Reader, Wallac Victor

4. Typical Procedure

-   Day 0: Seed 3000 U-87MG cells (cultured in RPMI/10% FCS) in 150 μl    medium into a 96-well plate, flat bottom (include mediumblank).    Incubate plates at 37° C. in a CO₂ incubator overnight.-   Day 1: Dilute compounds to a concentration 80 μM->1:5 in medium, 7    dilution steps, in 96-well plates.    -   Add 50 μl per well of each dilution (total volume per well 200        μl; final conc. of cpds: 20 μM->1:5). If required, test further        dilutions.    -   All concentrations are tested in duplicates or triplicates.    -   Controls: Cells w/o cpd. (+50 μl medium+DMSO).    -   Cells are incubated with compounds for 3 days.-   Day 4: Aspirate off medium and replace with 100 μl of 1× dye binding    solution (22 μl CyQuant NF dye reagent added to 11 ml of 1×HBSS    buffer). Cover the microplate and incubate for 30-60 min. for    equilibration of dye-DNA binding. Measure the fluorescence intensity    in a microplate reader (excitation at 485 nm, emission detection at    530 nm).

5. Evaluation

-   -   Calculate EC₅₀ using GraphPad Prism (Fifty)

The substances of the present invention are PI3 kinase pathwayinhibitors, in particular of the serine/threonine kinase mTOR and/ormembers of the lipid kinase family Pi3K. On account of their biologicalproperties, the novel compounds of the general formula (1) and theirisomers and their physiologically tolerated salts are suitable fortreating diseases which are characterized by excessive or anomalous cellproliferation.

These diseases include, for example: viral infections (e.g. HIV andKaposi's sarcoma); inflammation and autoimmune diseases (e.g. colitis,arthritis, Alzheimer's disease, glomerulonephritis and wound healing);bacterial, fungal and/or parasitic infections; leukaemias, lymphomas andsolid tumours; skin diseases (e.g. psoriasis); bone diseases;cardiovascular diseases (e.g. restenosis and hypertrophy). In addition,the compounds are useful for protecting proliferating cells (e.g. haircells, intestinal cells, blood cells and progenitor cells) from DNAdamage due to irradiation, UV treatment and/or cytostatic treatment(Davis et al., 2001).

For example, the following cancer diseases can be treated with compoundsaccording to the invention, without, however, being restricted thereto:brain tumours, such as acoustic neurinoma, astrocytomas such as piloidastrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma,gemistocytic astrocytoma, anaplastic astrocytoma and glioblastomas,brain lymphomas, brain metastases, hypophyseal tumour such asprolactinoma, HGH (human growth hormone) producing tumour andACTH-producing tumour (adrenocorticotrophic hormone),craniopharyngiomas, medulloblastomas, meningiomas andoligodendrogliomas; nerve tumours (neoplasms) such as tumours of thevegetative nervous system such as neuroblastoma sympathicum,ganglioneuroma, paraganglioma (phaeochromocytoma and chromaffinoma) andglomus caroticum tumour, tumours in the peripheral nervous system suchas amputation neuroma, neurofibroma, neurinoma (neurilemoma, schwannoma)and malignant schwannoma, as well as tumours in the central nervoussystem such as brain and spinal cord tumours; intestinal cancer such asrectal carcinoma, colon carcinoma, anal carcinoma, small intestinetumours and duodenal tumours; eyelid tumours such as basalioma or basalcell carcinoma; pancreatic gland cancer or pancreatic carcinoma; bladdercancer or bladder carcinoma; lung cancer (bronchial carcinoma) such assmall-cell bronchial carcinomas (oat cell carcinomas) and non-small-cellbronchial carcinomas such as squamous epithelium carcinomas,adenocarcinomas and large-cell bronchial carcinomas; breast cancer suchas mammary carcinoma, such as infiltrating ductal carcinoma, colloidcarcinoma, lobular invasive carcinoma, tubular carcinoma, adenoid cysticcarcinoma, and papillary carcinoma; non-Hodgkin's lymphomas (NHL) suchas Burkitt's lymphoma, low-malignancy non-Hodkgin's lymphomas (NHL) andmucosis fungoides; uterine cancer or endometrial carcinoma or corpuscarcinoma; CUP syndrome (cancer of unknown primary); ovarian cancer orovarian carcinoma such as mucinous, endometrial or serous cancer; gallbladder cancer; bile duct cancer such as Klatskin's tumour; testicularcancer such as seminomas and non-seminomas; lymphoma (lymphosarcoma)such as malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas(NHL) such as chronic lymphatic leukaemia, hair cell leukaemia,immunocytoma, plasmocytoma (multiple myeloma), immunoblastoma, Burkitt'slymphoma, T-zone mycosis fungoides, large-cell anaplastic lymphoblastomaand lymphoblastoma; laryngeal cancer such as vocal cord tumours,supraglottal, glottal and subglottal laryngeal tumours; bone cancer suchas osteochondroma, chondroma, chrondoblastoma, chondromyxoidfibroma,osteoma, osteoid-osteoma, osteoblastoma, eosinophilic granuloma, giantcell tumour, chondrosarcoma, osteosarcoma, Ewing's sarcoma,reticulosarcoma, plasmocytoma, fibrous dysplasia, juvenile bone cyst andaneurysmatic bone cyst; head/neck tumours such as tumours of the lips,tongue, floor of the mouth, oral cavity, gingiva, pallet, salivaryglands, pharynx, nasal cavities, paranasal sinuses, larynx and middleear; liver cancer such as liver cell carcinoma or hepatocellularcarcinoma (HCC); leukaemias, such as acute leukaemias, such as acutelymphatic/lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML);chronic leukaemias such as chronic lymphatic leukaemia (CLL), chronicmyeloid leukaemia (CML); stomach cancer or stomach carcinoma such aspapillary, tubular and mucinous adenocarcinoma, signet ring cellcarcinoma, adenoid squamous cell carcinoma, small-cell carcinoma andundifferentiated carcinoma; melanomas such as superficially spreading,nodular malignant lentigo and acral lentiginous melanoma; renal cancer,such as kidney cell carcinoma or hypernephroma or Grawitz's tumour;oesophageal cancer or oesophageal carcinoma; cancer of the penis;prostate cancer; pharyngeal cancer or pharyngeal carcinomas such asnasopharyngeal carcinomas, oropharyngeal carcinomas and hypopharyngealcarcinomas; retinoblastoma; vaginal cancer or vaginal carcinoma;squamous epithelium carcinomas, adeno carcinomas, in situ carcinomas,malignant melanomas and sarcomas; thyroid gland carcinomas such aspapillary, follicular and medullary thyroid gland carcinoma, and alsoanaplastic carcinomas; spinalioma, prickle cell carcinoma and squamousepithelium carcinoma of the skin; thymomas, urethral cancer and vulvarcancer. The novel compounds can be used for the prevention or short-termor long-term treatment of the abovementioned diseases including, whereappropriate, in combination with other state-of-the-art compounds suchas other anti-tumour substances, cytotoxic substances, cellproliferation inhibitors, antiangiogenic substances, steroids orantibodies.

The compounds of the general formula (1) can be used on their own or incombination with other active compounds according to the invention and,where appropriate, in combination with other pharmacologically activecompounds as well. Chemotherapeutic agents which can be administered incombination with the compounds according to the invention include,without being restricted thereto, hormones, hormone analogs andantihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant,megestrol acetate, flutamide, nilutamide, bicalutamide,aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate,fludrocortisone, fluoxymesterone, medroxyprogesterone and octreotide),aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole,exemestane and atamestane), LHRH agonists and antagonists (e.g.goserelin acetate and luprolide), inhibitors of growth factors (growthfactors such as platelet-derived growth factor and hepatocyte growthfactor, examples of inhibitors are growth factor antibodies, growthfactor receptor antibodies and tyrosine kinase inhibitors, such asgefitinib, imatinib, lapatinib, Erbitux® and trastuzumab);antimetabolites (e.g. antifolates such as methotrexate and raltitrexed,pyrimidine analogs such as 5-fluorouracil, capecitabine and gemcitabine,purine and adenosine analogs such as mercaptopurine, thioguanine,cladribine and pentostatin, cytarabine and fludarabine); antitumourantibiotics (e.g. anthracyclines, such as doxorubicin, daunorubicin,epirubicin and idarubicin, mitomycin C, bleomycin, dactinomycin,plicamycin and streptozocin); platinum derivatives (e.g. cisplatin,oxaliplatin and carboplatin); alkylating agents (e.g. estramustine,meclorethamine, melphalan, chlorambucil, busulphan, dacarbazine,cyclophosphamide, ifosfamide and temozolomide, nitrosoureas such ascarmustine and lomustine and thiotepa); antimitotic agents (e.g. vincaalkaloids such as vinblastine, vindesine, vinorelbine and vincristine;and taxans such as paclitaxel and docetaxel); topoisomerase inhibitors(e.g. epipodophyllotoxins such as etoposide and etopophos, teniposide,amsacrine, topotecan, irinotecan and mitoxantrone) and variouschemotherapeutic agents such as amifostin, anagrelide, clodronate,filgrastin, interferon alpha, leucovorin, rituximab, procarbazine,levamisole, mesna, mitotan, pamidronate and porfimer.

Examples of suitable forms for use are tablets, capsules, suppositories,solutions, in particular solutions for injection (s.c., i.v., i.m.) andinfusion, syrups, emulsions or dispersible powders. In this connection,the proportion of the pharmaceutically active compound(s) should in eachcase be in the range of 0.1-90% by weight, preferably 0.5-50% by weight,of the total composition, that is in quantities which are sufficient toachieve the dosage range which is specified below. If necessary, thedoses mentioned can be given several times a day.

Appropriate tablets can be obtained, for example, by mixing the activecompound(s) with known auxiliary substances, for example inert diluents,such as calcium carbonate, calcium phosphate or lactose, disintegrants,such as maize starch or alginic acid, binders, such as starch orgelatine, lubricants, such as magnesium stearate or talc, and/or agentsfor achieving a depot effect, such as carboxymethyl cellulose, celluloseacetate phthalate or polyvinyl acetate. The tablets can also compriseseveral layers.

Correspondingly, sugar-coated tablets can be produced by coating cores,which have been prepared in analogy with tablets, with agents which arecustomarily used in sugar coatings, for example collidone or shellac,gum arabic, talc, titanium dioxide or sugar. The core can also compriseseveral layers in order to achieve a depot effect or to avoidincompatibilities. In the same way, the sugar coating can also compriseseveral layers in order to achieve a depot effect, with it beingpossible to use the auxiliary substances which are mentioned above inthe case of the tablets.

Syrups of the active compounds or active compound combinations accordingto the invention can additionally comprise a sweetening agent, such assaccharine, cyclamate, glycerol or sugar as well as a taste-improvingagent, e.g. flavouring agents such as vanillin or orange extract. Theycan also comprise suspension aids or thickeners, such as sodiumcarboxymethyl cellulose, wetting agents, for example condensationproducts of fatty alcohols and ethylene oxide, or protectants such asp-hydroxybenzoates.

Injection and infusion solutions are produced in a customary manner,e.g. while adding isotonizing agents, preservatives, such asp-hydroxybenzoates, or stabilizers, such as alkali metal salts ofethylenediaminetetraacetic acid, where appropriate using emulsifiersand/or dispersants, with it being possible, for example, to employ,where appropriate, organic solvents as solubilizing agents or auxiliarysolvents when using water as diluent, and aliquoted into injectionbottles or ampoules or infusion bottles.

The capsules, which comprise one or more active compounds or activecompound combinations, can, for example, be produced by mixing theactive compounds with inert carriers, such as lactose or sorbitol, andencapsulating the mixture in gelatine capsules. Suitable suppositoriescan be produced, for example, by mixing with excipients which areenvisaged for this purpose, such as neutral fats or polyethylene glycol,or their derivatives.

Auxiliary substances which may be mentioned by way of example are water,pharmaceutically unobjectionable organic solvents, such as paraffins(e.g. petroleum fractions), oils of vegetable origin (e.g. groundnut oilor sesame oil), monofunctional or polyfunctional alcohols (e.g. EtOH orglycerol), carrier substances such as natural mineral powders (e.g.kaolins, argillaceous earths, talc and chalk), synthetic mineral powders(e.g. highly disperse silicic acid and silicates), sugars (e.g. canesugar, lactose and grape sugar), emulsifiers (e.g. lignin, sulphitewaste liquors, methyl cellulose, starch and polyvinylpyrrolidone) andglidants (e.g. magnesium stearate, talc, stearic acid and sodium laurylsulphate).

Administration is effected in a customary manner, preferably orally ortransdermally, in particular and preferably orally. In the case of oraluse, the tablets can naturally also comprise, in addition to theabovementioned carrier substances, additives such as sodium citrate,calcium carbonate and dicalcium phosphate together with a variety offurther substances such as starch, preferably potato starch, gelatineand the like. It is furthermore also possible to use glidants, such asmagnesium stearate, sodium lauryl sulphate and talc, for the tableting.In the case of aqueous suspensions, a variety of taste improvers or dyescan also be added to the active compounds in addition to theabovementioned auxiliary substances.

For parenteral administration, it is possible to employ solutions of theactive compounds while using suitable liquid carrier materials. Thedosage for intravenous administration is 1-1000 mg per hour, preferablybetween 5 and 500 mg per hour.

Despite this, it may be necessary, where appropriate, to diverge fromthe abovementioned quantities, depending on the body weight or thenature of the route of administration, on the individual response to themedicament, on the nature of its formulation and on the time or intervalat which the administration is effected. Thus, it may, in some cases, besufficient to make do with less than the previously mentioned lowestquantity whereas, in other cases, the abovementioned upper limit has tobe exceeded. When relatively large quantities are being administered, itmay be advisable to divide these into several single doses which aregiven over the course of the day.

The following formulation examples illustrate the present inventionwithout, however, restricting its scope:

PHARMACEUTICAL FORMULATION EXAMPLES

A) Tablets per tablet Active compound in accordance with formula (1) 100mg Lactose 140 mg Maize starch 240 mg Polyvinylpyrrolidone  15 mgMagnesium stearate  5 mg 500 mg

The finely ground active compound, lactose and a part of the maizestarch are mixed with each other. The mixture is sieved, after which itis moistened with a solution of polyvinylpyrrolidone in water, kneaded,wet-granulated and dried. The granular material, the remainder of themaize starch and the magnesium stearate are sieved and mixed with eachother. The mixture is pressed into tablets of suitable shape and size.

B) Tablets per tablet Active compound in accordance with formula (1) 80mg Lactose 55 mg Maize starch 190 mg  Microcrystalline cellulose 35 mgPolyvinylpyrrolidone 15 mg Sodium carboxymethyl starch 23 mg Magnesiumstearate  2 mg 400 mg 

The finely ground active compound, a part of the maize starch, thelactose, microcrystalline cellulose and polyvinylpyrrolidone are mixedwith each other, after which the mixture is sieved and worked, togetherwith the remainder of the maize starch and water, into a granularmaterial, which is dried and sieved. The sodium carboxymethyl starch andthe magnesium stearate are then added to the granular material and mixedwith it, and the mixture is pressed into tablets of suitable size.

C) Ampoule solution Active compound in accordance with formula (1) 50 mgSodium chloride 50 mg Water for injection  5 mL

The active compound is dissolved, either at its intrinsic pH or, whereappropriate, at pH 5.5-6.5, in water after which sodium chloride isadded as isotonizing agent. The resulting solution is renderedpyrogen-free by filtration and the filtrate is aliquoted, under asepticconditions, into ampoules, which are then sterilized and sealed bymelting. The ampoules contain 5 mg, 25 mg and 50 mg of active compound.

1.-15. (canceled)
 16. A method of treating a disease comprisingadministering an effective amount of a compound of formula 1 or apharmaceutically acceptable salt thereof to a patient in need thereof,wherein:

R³ denotes a group selected from among 3-8 membered heterocycloalkyl,C₆₋₁₀aryl and 5-12 membered heteroaryl, optionally substituted by one ormore identical or different R⁴; and R¹ denotes a group selected fromamong C₆₋₁₀aryl and 5-12 membered heteroaryl, optionally substituted byone or more identical or different R⁵ and R² denotes a group selectedfrom among hydrogen, C₁₋₄alkyl, C₃₋₈cycloalkyl, 3-8 memberedheteroalkyl, 3-8 membered heterocycloalkyl, —OR^(v), —NR^(v)R^(v1),—SR^(v), —CF₃, —CN, —NC and —NO₂, and each R⁴ denotes a group selectedfrom among R^(a) and R^(b); and each R^(a) independently of one anotherdenotes hydrogen or a group selected from among C₁₋₆alkyl, 2-6 memberedheteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl,C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 membered heteroaryl, 6-18 memberedheteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 memberedheterocycloalkylalkyl, R^(a) optionally being substituted by one or moreidentical or different R^(b) and/or R^(c4), each R^(b) denotes asuitable group and is selected independently of one another from among═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃, —OCHF₂, ═S, —SR^(c), ═NR^(c),═NOR^(c), ═NNR^(c)R^(c1), ═NN(R^(g))C(O)NR^(c)R^(c1), —NR^(c)R^(c1),—ONR^(c)R^(c1), —N(OR^(c))R^(c1), —N(R^(g))NR^(c)R^(c1), halogen, —CF₃,—CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(c), —S(O)OR^(c),—S(O)₂R^(c), —S(O)₂OR^(c), —S(O)NR^(c)R^(c1), —S(O)₂NR^(c)R^(c1),—OS(O)R^(c), —OS(O)₂R^(c), —OS(O)₂OR^(c), —OS(O)NR^(c)R^(c1),—OS(O)₂NR^(c)R^(c1), —C(O)R^(c), —C(O)OR^(c), —C(O)SR^(c),—C(O)NR^(c)R^(c1), —C(O)N(R^(g))NR^(c)R^(c1), —C(O)N(R^(g))OR^(c),—C(NR^(g))NR^(c)R^(c1), —C(NOH)R^(c), —C(NOH)NR^(c)R^(c1), —OC(O)R^(c),—OC(O)OR^(c), —OC(O)SR^(c), —OC(O)NR^(c)R^(c1), —OC(NR^(g))NR^(c)R^(c1),—SC(O)R^(c), —SC(O)OR^(c), —SC(O)NR^(c)R^(c), —SC(NR^(g))NR^(c)R^(c1),—N(R^(g))C(O)R^(c), —N[C(O)R^(c)][C(O)R^(c1)], —N(OR^(g))C(O)R^(c),—N(R^(g))C(NR^(g1))R^(c), —N(R^(g))N(R^(g1))C(O)R^(c),—N[C(O)R^(c2)]NR^(c)R^(c1), —N(R^(g))C(S)R^(c), —N(R^(g))S(O)R^(c),—N(R^(g))S(O)OR^(c), —N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)][S(O)₂R^(c1)],—N(R^(g))S(O)₂OR^(c), —N(R^(g))S(O)₂NR^(c)R^(c1),—N(R^(g))[S(O)₂]₂R^(c), —N(R^(g))C(O)OR^(c), —N(R^(g))C(O)SR^(c),—N(R^(g))C(O)NR^(c)R^(c1), —N(R^(g))C(O)NR^(g1)NR^(c)R^(c1),—N(R^(g))N(R^(g1))C(O)NR^(c)R^(c1), —N(R^(g))C(S)NR^(c)R^(c1),—[N(R^(g))C(O)]₂R^(c), —N(R^(g))[C(O)]₂R^(c),—N{[C(O)]₂R^(c)}{[C(O)₂R^(c1)}, —N(R^(g))[C(O)]₂OR^(c),—N(R^(g))C(O)]₂NR^(c)R^(c), —N{[C(O)]₂OR^(c)}{[C(O)]₂OR^(c1)},—N{[C(O)]₂NR^(c)R^(c1)}{[C(O)]₂NR^(c2)R^(c3)}, —[N(R^(g))C(O)]₂OR^(c),—N(R^(g))C(NR^(g1))OR^(c), —N(R^(g))C(NOH)R^(c),—N(R^(g))C(NR^(g1))SR^(c), —N(R^(g))C(NR^(g1))NR^(c)R^(c1),—N(R^(g))C(═N—CN)NR^(c)R^(c1) and —N═C(R^(g))NR^(c)R^(c1) and eachR^(c), R^(c1), R^(c2), R^(c3) and R^(c4) independently of one anotherdenotes hydrogen or a group selected from among C₁₋₆alkyl, 2-6 memberedheteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl,C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 membered hetero-aryl, 6-18 memberedheteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 memberedheterocycloalkylalkyl, R^(c), R^(c1), R^(c2), R^(c3) and R^(c4)independently optionally being substituted by one or more identical ordifferent R^(d) and/or R^(e4), where R^(c) together with R^(g) and/orR^(c1) and/or R^(c2) and/or R^(c3) or R^(c2) together with R^(c3) mayform a 3-8 membered heterocyclalkyl residue via a shared C-, N-, O- orS-atom, and each R^(d) denotes a suitable group and is selectedindependently of one another from among ═O, —OR^(e), C₁₋₃haloalkyloxy,—OCF₃, —OCHF2, ═S, —SR^(e), ═NR^(e), ═NOR^(e), ═NNR^(e)R^(e1),═NN(R^(g2))C(O)NR^(e)R^(e1), —NR^(e)R^(e1), —ONR^(e)R^(e1),—N(R^(g2))NR^(e)R^(e1), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(e), —S(O)OR^(e), —S(O)₂R^(e), —S(O)₂OR^(e),—S(O)NR^(e)R^(e1), —S(O)₂NR^(e)R^(e1), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)₂OR^(e), —OS(O)NR^(e)R^(e1), —OS(O)₂NR^(e)R^(e1), —C(O)R^(e),—C(O)OR^(e), —C(O)SR^(e), —C(O)NR^(e)R^(e1), —C(O)N(R^(g2))NR^(e)R^(e1),—C(O)N(R^(g2))OR^(e), —C(NR^(g2))NR^(e)R^(e1), —C(NOH)R^(e),—C(NOH)NR^(e)R^(e1), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)SR^(e),—OC(O)NR^(e)R^(e1), —OC(NR^(g2))NR^(e)R^(e1), —SC(O)R^(e), —SC(O)OR^(e),—SC(O)NR^(e)R^(e1), —SC(NR^(g2))NR^(e)R^(e1), —N(R^(g2))C(O)R^(e),—N[C(O)R^(e)][C(O)R^(e1)], —N(OR^(g2))C(O)R^(e), —N(R²C(NR^(g3))R^(e),—N(R^(g2))N(R^(g3))C(O)R^(e), —N[C(O)R^(e2)]NR^(e)R^(e1),—N(R^(g2))C(S)R^(e), —N(R^(g2))S(O)R^(e),—N(R^(g2))S(O)OR^(e)—N(R^(g2))S(O)₂R^(e), —N[S(O)₂R^(e)][S(O)₂R^(e1)],—N(R^(g2))S(O)₂OR^(e), —N(R^(g2))S(O)₂NR^(e)R^(e1),—N(R^(g2))[S(O)₂]₂R^(e), —N(R^(g2))C(O)OR^(e), —N(R^(g2))C(O)SR^(e),—N(R^(g2))C(O)NR^(e)R^(e1), —N(R^(g2))C(O)NR^(g3)NR^(e)R^(e1),—N(R^(g2))N(R^(g3))C(O)NR^(e)R^(e1), —N(R^(g2))C(S)NR^(e)R^(e1),—[N(R^(g2))C(O)][N(R^(g3))C(O)]R^(e), —N(R^(g2))[C(O)]₂R^(e),—N{[C(O)]₂R^(e)}{[C(O)]₂R^(e1)}, —N(R^(g2))[C(O)]₂OR^(e),—N(R^(g2))[C(O)]₂NR^(e)R^(e1), —N{[C(O)]₂OR^(e)}{[C(O)]₂OR^(e)},—N{[C(O)]₂NR^(e)R^(e1)}{[C(O)]₂NR^(e2)R^(e3)},—[N(R^(g3))C(O)][N(R^(g3))C(O)]OR^(e), —N(R^(g))C(NR^(g3))OR^(e),—N(R^(g))C(NOH)R^(e), —N(R^(g2))C(NR^(g3))SR^(e),—N(R^(g2))C(NR^(g3))NR^(e)R^(e1), —N(R^(g2))C(═N—CN)NR^(e)R^(e1) and—N═C(R^(g2))NR^(e)R^(e1) each R^(e), R^(e1), R^(e2), R^(e3) and R^(e4)independently of one another denotes hydrogen or a group selected fromamong C₄₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12membered hetero-aryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, where R^(e)together with R^(g2) and/or R^(e1) and/or R^(e2) and/or R^(e3) or R^(e2)together with R^(e3) may form a 3-8 membered heterocyclalkyl residue viaa shared C-, N-, O- or S-atom, and where R^(e), R^(e1), R^(e2), R^(e3)and R^(e4) independently optionally being substituted by one or moreidentical or different R^(f) and/or R^(g6), and each R^(f) denotes asuitable group and in each case is selected independently of one anotherfrom among ═O, —OR^(g), C₁₋₃haloalkyloxy, —OCF₃, —OCHF₂, ═S, —SR^(g),═NR^(g4), ═NOR^(g4), ═NNR^(g4)R^(g5), ═NN(R^(h))C(O)NR^(g4)R^(g5),—NR^(g4)R^(g5), —ONR^(g4)R^(g5), —N(R^(h))NR^(g4)R^(g5), halogen, —CF₃,—CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(g4), —S(O)OR^(g4),—S(O)₂R^(g4), —S(O)₂OR^(g4), —S(O)NR^(g4)R^(g5), —S(O)₂NR^(g4)R^(g5),—OS(O)R^(g4), —OS(O)₂R^(g4), —OS(O)₂OR^(g4), —OS(O)NR^(g4)R^(g5),—OS(O)₂NR^(g4)R^(g5), —C(O)R^(g4), —C(O)OR^(g4), —C(O)SR^(g4),—C(O)NR^(g4)R^(g5), —C(O)N(R^(h))NR^(g4)R^(g5), —C(O)N(R^(h))OR^(g4),—C(NR^(h))NR^(g4)R^(g5), —C(NOH)R^(g4), —C(NOH)NR^(g4)R^(g5),—OC(O)R^(g4), —OC(O)OR^(g4), —OC(O)SR^(g4), —OC(O)NR^(g4)R^(g5),—OC(NR^(h))NR^(g4)R^(g5), —SC(O)R^(g4), —SC(O)OR^(g4),—SC(O)NR^(g4)R^(g5), —SC(NR^(h))NR^(g4)R^(g5), —N(R^(h))C(O)R^(g4),—N[C(O)R^(g4)]₂, —N(OR^(h))C(O)R^(g4), —N(R^(h))C(NR^(h1))R^(g4),—N(R^(h))N(R^(h1))C(O)R^(g4), —N[C(O)R^(g6)]NR^(g4)R^(g5),—N(R^(h))C(S)R^(g4), —N(R^(h))S(O)R^(g4), —N(R^(h))S(O)OR^(g4),—N(R^(h))S(O)₂R^(g4), —N[S(O)₂R^(g4)][S(O)₂R^(g5)],—N(R^(h))S(O)₂R^(g4), —N(R^(h))S(O)₂NR^(g4)R^(g5),—N(R^(h))[S(O)₂]₂R^(g4), —N(R^(h))C(O)OR^(g4), —N(R^(h))C(O)SR^(g4),—N(R^(h))C(O)NR^(g4)R^(g5), —N(R^(h))C(O)NR^(h1)NR^(g4)R^(g5),—N(R^(h))N(R^(h1))C(O)NR^(g4)R^(g5), —N(R^(h))C(S)NR^(g4)R^(g5),—[N(R^(h))C(O)][N(R^(h1))C(O)]R^(g4), —N(R^(h))[C(O)]₂R^(g4),—N{[C(O)]₂R^(g4)}{[C(O)]₂R^(g5)}, —N(R^(h))[C(O)]₂OR^(g4),—N(R^(h))[C(O)]₂NR^(g4)R^(g5), —N{[C(O)]₂OR⁴}{[C(O)]₂OR^(g4)},—N{[C(O)]₂NR^(g4)R^(g5)}{[C(O)]₂NR^(g4)R^(g5)},—[N(R^(h))C(O)][N(R^(h1))C(O)]OR^(g4), —N(R^(h))C(NR^(h1))OR^(g4),—N(R^(h))C(NOH)R^(g4), —N(R^(h))C(NR^(h1))SR^(g4),—N(R^(h))C(NR^(h1))NR^(g4)R^(g5), —N(R^(h))C(═N—CN)NR^(g4)R^(g5) and—N═C(R^(h))NR^(g4)R^(g5); and each R^(g), R^(g1), R^(g2), R^(g3),R^(g4), R^(g5) and R^(g6) independently of one another denotes hydrogenor a group selected from among C₄₋₆alkyl, 2-6 membered heteroalkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 5-12 membered hetero-aryl, 6-18 memberedheteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 memberedheterocycloalkylalkyl, where R^(g) together with R^(g1) and/or R^(h) mayform a 3-8 membered cycloalkyl or a 3-8 membered heterocyclalkyl residuevia a shared C-, N-, O- or S-atom, and where R^(g), R^(g1), R^(g2),R^(g3), R^(g4), R^(g5) and R^(g6) independently optionally beingsubstituted by one or more identical or different R^(h2); and eachR^(h), R^(h1) and R^(h2) is selected independently of one another fromamong hydrogen, C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, where R^(h)together with R^(h1) may form a 3-8 membered cycloalkyl or a 3-8membered heterocyclalkyl residue via a shared C-, N-, O- or S-atom, andeach R⁵ denotes a group selected from among R^(m) and R^(n); and eachR^(m) independently of one another denotes hydrogen or a group selectedfrom among C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₄₋₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, and R^(m)optionally substituted by one or more identical or different R^(n)and/or R^(o4), each R^(n) denotes a suitable group and is selectedindependently of one another from among ═O, —OR^(o), C₁₋₃haloalkyloxy,—OCF₃, —OCHF₂, ═S, —SR^(o), ═NR^(o), ═NOR^(o), ═NNR^(o)R^(o1),═NN(R^(s))C(O)NR^(o)R^(o1), —NR^(o)R^(o1), —ONR^(o)R^(o1),—N(OR^(o))R^(o1), —N(R^(s))NR^(o)R^(o1), halogen, —CF₃, —CN, —NC, —OCN,—SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(o), —S(O)OR^(o), —S(O)₂R^(o),—S(O)₂OR^(o), —S(O)NR^(o)R^(o1), —S(O)₂NR^(o)R^(o1), —OS(O)R^(o),—OS(O)₂R^(o), —OS(O)₂OR^(o), —OS(O)NR^(o)R^(o1), —OS(O)₂NR^(o)R^(o1),—C(O)R^(o), —C(O)OR^(o), —C(O)SR^(o), —C(O)NR^(o)R^(o1),—C(O)N(R^(s))NR^(o)R^(o1), —C(O)N(R^(s))OR^(o), —C(NR^(s))NR^(o)R^(o1),—C(NOH)R^(o), —C(NOH)NR^(o)R^(o1), —OC(O)R^(o), —OC(O)OR^(o),—OC(O)SR^(o), —OC(O)NR^(o)R^(o1), —OC(NR^(s))NR^(o)R^(o1), —SC(O)R^(o),—SC(O)OR^(o), —SC(O)NR^(o)R^(o), —SC(NR^(s))NR^(o)R^(o1),—N(R^(s))C(O)R^(o), —N[C(O)R^(o)][C(O)R^(o1)], —N(OR^(s))C(O)R^(o),—N(R^(s))C(NR^(s1))R^(o), —N(R^(s))N(R^(s1))C(O)R^(o),—N[C(O)R^(o2)]NR^(o)R^(o1), —N(R^(s))C(S)R^(o), —N(R^(s))S(O)R^(o),—N(R^(s))S(O)OR^(o), —N(R^(s))S(O)₂R^(o), —N[S(O)₂R^(o)][S(O)₂R^(o1)],—N(R^(s))S(O)₂OR^(o), —N(R^(s))S(O)₂NR^(o)R^(o1),—N(R^(s))[S(O)₂]₂R^(o), —N(R^(s))C(O)OR^(o), —N(R^(s))C(O)SR^(o),—N(R^(s))C(O)NR^(o)R^(o1), —N(R^(s))C(O)NR^(s1)NR^(o)R^(o1),—N(R^(s))N(R^(s1))C(O)NR^(o)R^(o1), —N(R^(s))C(S)NR^(o)R^(o1),—[N(R^(s))C(O)]₂R^(o), —N(R^(s))[C(O)]₂R^(o),—N{[C(O)]₂R^(o)}{[C(O)]₂R^(o1)}, —N(R^(s))[C(O)]₂OR,—N(R^(s))[C(O)]₂NR^(o)R^(o1), —N{[C(O)]₂OR^(o)}{[C(O)]₂OR^(o1)},—N{[C(O)]₂NR^(o)R^(o1)}{[C(O)]₂NR^(o2)R^(o3)}, —[N(R^(s))C(O)]₂OR^(o),—N(R^(s))C(NR^(s1))OR^(o), —N(R^(s))C(NOH)R^(o),—N(R^(s))C(NR^(s1))SR^(o), —N(R^(s))C(NR^(s1))NR^(o)R^(o1) and—N═C(R^(s))NR^(o)R^(o1) and each R^(o), R^(o1), R^(o2) and R^(o3)independently of one another denotes hydrogen or a group selected fromamong C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12membered hetero-aryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, where R^(o)together with R^(o1) and/or R^(s) and/or R^(c1) and/or R^(c2) and/orR^(c3) or R^(c2) together with R^(c3) may form a 3-8 membered mono- orbicyclic heterocyclalkyl residue via a shared C-, N-, O- or S-atom, orwhere R^(o) together with R^(o1) may form a 3-14 membered spirocyclicheterocyclalkyl residue via a shared C-, N-, O- or S-atom and whereR^(o), R^(o1), R^(o2) and R^(o3) independently optionally beingsubstituted by one or more identical or different R^(P) and/or R^(q4),and each R^(P) denotes a suitable group and is selected independently ofone another from among ═O, —OR^(q), C₁₋₃haloalkyloxy, —OCF₃, —OCHF₂, ═S,—SR^(q), ═NR^(q), ═NOR^(q), ═NNR^(q)R^(q1), ═NN(R^(s))C(O)NR^(q)R^(q1),—NR^(q)R^(q1), —ONR^(q)R^(q1), —N(R^(s))NR^(q)R^(q1), halogen, —CF₃,—CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(q), —S(O)OR^(q),—S(O)₂R^(q), —S(O)₂OR^(q), —S(O)NR^(q)R^(q1), —S(O)₂NR^(q)R^(q1),—OS(O)R^(q), —OS(O)₂R^(q), —OS(O)₂OR^(q), —OS(O)NR^(q)R^(q1),—OS(O)₂NR^(q)R^(q1), —C(O)R^(q), —C(O)OR^(q), —C(O)SR^(q),—C(O)NR^(q)R^(q1), —C(O)N(R^(s))NR^(q)R^(q1), —C(O)N(R^(s))OR^(q),—C(NR^(s))NR^(q)R^(q1), —C(NOH)R^(q), —C(NOH)NR^(q)R^(q1), —OC(O)R^(q),—OC(O)OR^(q), —OC(O)SR^(q), —OC(O)NR^(q)R^(q1), —OC(NR^(s))NR^(q)R^(q1),—SC(O)R^(q), —SC(O)OR^(q), —SC(O)NR^(q)R^(q1), —SC(NR^(s))NR^(q)R^(q1),—N(R^(s))C(O)R^(q), —N[C(O)R^(q)][C(O)R^(q1)], —N(OR^(s))C(O)R^(q),—N(R^(s))C(R^(s1))R^(q), —N(R^(s))N(R^(s1))C(O)R^(q),—N[C(O)R^(q2)]NR^(q)R^(q1), —N(R^(s))C(S)R^(q), —N(R^(s))S(O)R^(q),—N(R^(s))S(O)OR^(q), —N(R^(s))S(O)₂R^(q), —N[S(O)₂R^(q)][S(O)₂R^(q1)],—N(R^(s))S(O)₂OR^(q), —N(R^(s))S(O)₂NR^(q)R^(q1),—N(R^(s))[S(O)₂]₂R^(q), —N(R^(s))C(O)OR^(q), —N(R^(s))C(O)SR^(q),—N(R^(s))C(O)NR^(q)R^(q1), —N(R^(s))C(O)NR^(s1)NR^(q)R^(q1),—N(R^(s))N(R^(s1))C(O)NR^(q)R^(q1), —N(R^(s))C(S)NR^(q1),—[N(R^(s))C(O)][N(R^(g1))C(O)]R^(q), —N(R^(s))[C(O)]₂R^(q),—N{[C(O)]₂R^(q)}{[C(O)]₂R^(q1)}, —N(R^(s))[C(O)]₂OR^(q),—N(R^(s))[C(O)]₂NR^(q)R^(q1), —N{[C(O)]₂OR^(q)}{[C(O)]₂OR^(q1)},—N{[C(O)]₂NR^(q)R^(q1)}{[C(O)]₂NR^(q2)R^(q3)},—[N(R^(s))C(O)][N(R^(s1))C(O)]OR^(q), —N(R^(s))C(NR^(s1))OR^(q),—N(R^(s))C(NOH)R^(q), —N(R^(s))C(NR^(s1))SR^(q),—N(R^(s))C(NR^(s1))NR^(q)R^(q1), —N(R^(s))C(═N—CN)NR^(q)R^(q1) and—N═C(R^(s))NR^(q)R^(q1), and each R¹, R^(q1), R^(q2), R^(q3) and R^(q4)independently of one another denotes hydrogen or a group selected fromamong C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12membered hetero-aryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, where R^(q)together with R^(q1) and/or R^(q2) and/or R^(q3) and/or R^(s) may form a3-8 membered heterocyclalkyl residue via a shared C-, N-, O- or S-atom,wherein R^(q), R^(q1), R^(q2), R^(q3) and R^(q4) are optionallyindependently substituted by one or more identical or different R^(r)and/or R^(s4), and each R^(r) denotes a suitable group and in each caseis selected independently of one another from among ═O, —OR^(s),C₁₋₃haloalkyloxy, —OCF₃, —OCHF₂, ═S, —SR^(s), ═NR^(s), ═NOR^(s),═NNR^(s)R^(s1), ═NN(R^(t))C(O)NR^(s)R^(s1), —NR^(s)R^(s1),—ONR^(s)R^(s1), —N(R^(h))NR^(s)R^(s1), halogen, —CF₃, —CN, —NC, —OCN,—SCN, —NO, —NO₂, —N₂, —N₃, —S(O)R^(s), —S(O)OR^(s), —S(O)₂R^(s),—S(O)₂OR^(s), —S(O)NR^(s)R^(s1), —S(O)₂NR^(s)R^(s1), —OS(O)R^(s),—OS(O)₂R^(s), —OS(O)₂OR^(s), —OS(O)NR^(s)R^(s1), —OS(O)₂NR^(s)R^(s1),—C(O)R^(s), —C(O)OR^(s), —C(O)SR^(s), —C(O)NR^(s)R^(s1),—C(O)N(R^(t))NR^(s)R^(s1), —C(O)N(R^(t))OR^(s), —C(NR^(t))NR^(s)R^(s1),—C(NOH)R^(s), —C(NOH)NR^(s)R^(s1), —OC(O)R^(s), —OC(O)OR^(s),—OC(O)SR^(s), —OC(O)NR^(s)R^(s1), —OC(NR^(t))NR^(s)R^(s1), —SC(O)R^(s),—SC(O)OR^(s), —SC(O)NR^(s)R^(s1), —SC(NR^(t))NR^(s)R^(s1),—N(R^(t))C(O)R^(s), —N[C(O)R^(s)][C(O)R^(s1)], —N(OR^(t))C(O)R^(s),—N(R^(t))C(NR^(t1))R^(s), —N(R^(t))N(R^(t1))C(O)R^(s),—N[C(O)R^(g2)]NR^(s)R^(s1), —N(R^(t))C(S)R^(s), —N(R^(t))S(O)R^(s),—N(R^(t))S(O)OR^(s), —N(R^(t))S(O)₂R^(s), —N[S(O)₂R^(s)][S(O)₂R^(s1)],—N(R^(t))S(O)₂OR^(s), —N(R^(t))S(O)₂NR^(s)R^(s1),—N(R^(t))[S(O)₂]₂R^(s), —N(R^(t))C(O)OR^(s), —N(R^(t))C(O)SR^(s),—N(R^(t))C(O)NR^(s)R^(s1), —N(R^(t))C(O)NR^(t1)NR^(s)R^(s1),—N(R^(t))N(R^(t1))C(O)NR^(s)R^(s1), —N(R^(t))C(S)NR^(s)R^(s1),—[N(R^(t))C(O)][N(R^(h1))C(O)]R^(s), —N(R^(t))[C(O)]₂R^(s),—N{[C(O)]₂R^(s)}{[C(O)]₂R^(s1)}, —N(R^(t))[C(O)]₂OR^(s),—N(R^(t))[C(O)]₂NR^(s)R^(s1), —N{[C(O)]₂OR^(s)}{[C(O)]₂OR^(s1)},—N{[C(O)]₂NR^(s)R^(s1)}{[C(O)]₂NR^(s2)R^(s3)},—[N(R^(t))C(O)][N(R^(t1))C(O)]OR^(s), —N(R^(t))C(NR^(t1))OR^(s),—N(R^(t))C(NOH)R^(s), —N(R^(t))C(NR^(t1))SR^(s),—N(R^(t))C(NR^(t1))NR^(s)R^(s1), —N(R^(t))C(═N—CN)NR^(s)R^(s1) and—N═C(R^(t))NR^(s)R^(s1); and each R^(s), R^(s1), R^(s2), R^(s3) andR^(s4) independently of one another denotes hydrogen or a group selectedfrom among C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12membered hetero-aryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, where R^(s)together with R^(s1) and/or R^(s2) and/or R^(s3) and/or R^(t) may form a3-8 membered heterocyclalkyl residue via a shared C-, N-, O- or S-atom,R^(s), R^(s1), R^(s2), R^(s3) and R^(s4) independently optionally beingsubstituted by one or more identical or different R^(t2); and eachR^(t), R^(t1) and R^(t2) is selected independently of one another fromamong hydrogen, C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, where R^(t)together with R^(t1) may form a 3-8 membered heterocyclalkyl residue viaa shared C-, N-, O- or S-atom, and each R^(v) and R^(v1) is selectedindependently of one another from among hydrogen, C₁₋₆alkyl, 2-6membered heteroalkyl, C₁₋₈haloalkyl, where R^(v) together with R^(v1)may form a 3-8 membered heterocyclalkyl residue via a shared C-, N-, O-or S-atom, optionally in the form of the prodrugs, the tautomers, theracemates, the enantiomers, the diastereomers, the prodrugs and themixtures thereof, and optionally the pharmacologically acceptable saltsthereof.
 17. The method of claim 16 wherein said disease is aproliferative disease.
 18. (canceled)
 19. The method of claim 16 whereinsaid disease is selected from a group consisting of cancer, infections,inflammatory and autoimmune diseases.
 20. The method of treating adisease selected from a group consisting of cancer, infections,inflammatory and autoimmune diseases, comprising administering aneffective amount of a compound of formula 1 or a pharmaceuticallyacceptable salt thereof and pharmaceutically acceptable excipientsand/or carriers, to a patient in need thereof.
 21. (canceled)